16-89746685-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):c.3412C>G(p.Leu1138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,614,004 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. L1138F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (13 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 3.07

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011628985).
• BP6: Variant 16-89746685-G-C is Benign according to our data. Variant chr16-89746685-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 134265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000696 (106/152356) while in subpopulation SAS AF= 0.0106 (51/4824). AF 95% confidence interval is 0.00826. There are 2 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.3412C>G	p.Leu1138Val	missense_variant	35/43	ENST00000389301.8
FANCA	NM_001286167.3	c.3412C>G	p.Leu1138Val	missense_variant	35/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.3412C>G	p.Leu1138Val	missense_variant	35/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152238 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00150 AC: 377 AN: 251228 Hom.: 5 AF XY: 0.00189 AC XY: 257 AN XY: 135796

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00928

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000833 AC: 1217 AN: 1461648 Hom.: 13 Cov.: 31 AF XY: 0.00115 AC XY: 836 AN XY: 727144

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152356 Hom.: 2 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74496

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000272 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: FANCA c.3412C>G (p.Leu1138Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251228 control chromosomes, predominantly at a frequency of 0.0093 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCA p.Leu1138Val variant was identified in 1 of 90 proband chromosomes (frequency: 0.011) from individuals with breast cancer (Jalkh_2017_PMID:28202063). The variant was identified in dbSNP (ID: rs138417003) and ClinVar (classified as benign by Invitae, as likely benign by Counsyl and as uncertain significance by Illumina). The variant was identified in control databases in 390 of 282634 chromosomes (5 homozygous) at a frequency of 0.00138 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 284 of 30614 chromosomes (freq: 0.009277), Other in 13 of 7222 chromosomes (freq: 0.0018), Latino in 30 of 35420 chromosomes (freq: 0.000847), African in 18 of 24960 chromosomes (freq: 0.000721) and European (non-Finnish) in 45 of 129076 chromosomes (freq: 0.000349), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Leu1138 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, 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 benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 14, 2018	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

FANCA: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	19
Dann	Benign	0.91
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.18	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.91	P;.
Vest4		0.26
MVP		0.89
ClinPred		0.043	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.34

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: rs138417003; hg19: chr16-89813093; COSMIC: COSV59796302; COSMIC: COSV59796302;