rs17227396

chr16-89739264-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):c.4036G>A(p.Ala1346Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,614,124 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1346V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (95 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10 O:1
• Conservation: PhyloP100: 0.180

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029540062).
• BP6: Variant 16-89739264-C-T is Benign according to our data. Variant chr16-89739264-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89739264-C-T is described in Lovd as [Pathogenic]. Variant chr16-89739264-C-T is described in Lovd as [Likely_benign]. Variant chr16-89739264-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00185 (282/152324) while in subpopulation SAS AF= 0.0429 (207/4828). AF 95% confidence interval is 0.0381. There are 9 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.4036G>A	p.Ala1346Thr	missense_variant	41/43	ENST00000389301.8
ZNF276	NM_001113525.2	c.*1018C>T		3_prime_UTR_variant	11/11	ENST00000443381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.4036G>A	p.Ala1346Thr	missense_variant	41/43	1	NM_000135.4	P1
ZNF276	ENST00000443381.7	c.*1018C>T		3_prime_UTR_variant	11/11	1	NM_001113525.2	P2

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152206 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0430

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00478 AC: 1200 AN: 251304 Hom.: 32 AF XY: 0.00656 AC XY: 891 AN XY: 135844

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00235 AC: 3438 AN: 1461800 Hom.: 95 Cov.: 35 AF XY: 0.00342 AC XY: 2490 AN XY: 727200

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0365

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152324 Hom.: 9 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74480

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000262 Hom.: 1

Bravo AF: 0.000714

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00522 AC: 634

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: FANCA c.4036G>A (p.Ala1346Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 1607150 control chromosomes, predominantly at a frequency of 0.037 within the South Asian subpopulation in the gnomAD database (v4.0 dataset), including 104 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17-fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Although reported in the literature, to our knowledge, no compelling evidence supporting a pathogenic outcome has been ascertained for c.4036G>A in individuals affected with Fanconi Anemia, and no experimental evidence demonstrating its impact on protein function have been reported. Ten other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all classified this variant as Benign/Likely Benign. Based on the evidence outlined above, the variant was classified as benign. -

Fanconi anemia complementation group A Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan de Winter. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	FANCA: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCA p.Ala1346Thr variant was identified in probands affected by Fanconi Anemia. The variant was identified in 2 out of 122 proband chromosomes (frequency = 0.016) among Indian patients affected by Fanconi Anemia (Solanki_2016_PMID: 26799702). The variant was also identified in 1 out of 80 proband chromosomes (frequency = 0.006) in a compound heterozygous state among patients affected by Fanconi Anemia whose ethnicity was not specified (Ameziane_2008_PMID: 17924555). The variant was also identified in the Geno2MP database, found in a heterozygous state in 18 affected individuals and in a homozygous state in 1 affected individual. The variant was also identified in a heterozygous state in 4 relatives of affected individuals. The p.Ala1346Thr variant was identified in dbSNP (ID: rs17227396) as “With other allele.” The p.Ala1346Thr variant was identified in ClinVar, and was classified as likely benign by Illumina in 2016 and as benign by Invitae in 2017. The variant was found in the ClinVitae (reported as “Conflicting Interpretations of Pathogenicity”) and LOVD 3.0 (reported as “Affects function”) databases. The variant was not identified in COGR, Cosmic, or MutDB databases. The p.Ala1346Thr variant was identified in control databases in 1215 of 282704 chromosomes (32 homozygous) at a frequency of 0.004298 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1150 of 30614 chromosomes (freq: 0.03756), Other in 18 of 7224 chromosomes (freq: 0.002492), African in 35 of 24956 chromosomes (freq: 0.001402), Latino in 5 of 35428 chromosomes (freq: 0.000141), East Asian in 2 of 19946 chromosomes (freq: 0.0001), European (non-Finnish) in 5 of 129056 chromosomes (freq: 0.000039), while the variant was not observed in the Ashkenazi Jewish, and European (Finnish) populations. The p.Ala1346 residue is not conserved in mammals and four out of fivecomputational analyses (SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign. References: Solanki A, Mohanty P, Shukla P, Rao A, Ghosh K, Vundinti BR. FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients. PLoS One. 2016 Jan 22;11(1):e0147016. doi: 10.1371/journal.pone.0147016. eCollection 2016. PubMed PMID: 26799702; PubMed Central PMCID: PMC4723128 Ameziane N, Errami A, Léveillé F, Fontaine C, de Vries Y, van Spaendonk RM, de Winter JP, Pals G, Joenje H. Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat. 2008 Jan;29(1):159-66. PubMed PMID: 17924555. Geno2MP, NHGRI/NHLBI University of Washington-Center for Mendelian Genomics (UW-CMG), Seattle, WA (URL: http://geno2mp.gs.washington.edu [Accessed November 28, 2018]. -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	3.3
Dann	Benign	0.69
DEOGEN2	Benign	0.13	T;.;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.59	T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;T;T;D
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.46	P;.;.;.
Vest4		0.091
MVP		0.93
ClinPred		0.0060	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17227396; hg19: chr16-89805672; COSMIC: COSV104613999; COSMIC: COSV104613999;