16-89810978-G-C

Position:

• chr16-89810978-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000135.4(FANCA):​c.377C>G​(p.Thr126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: -0.650

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]

FANCA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006103754).
• BP6: Variant 16-89810978-G-C is Benign according to our data. Variant chr16-89810978-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408185.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.377C>G	p.Thr126Arg	missense_variant	4/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.377C>G	p.Thr126Arg	missense_variant	4/43		NP_001273096.1
FANCA	NM_001018112.3	c.377C>G	p.Thr126Arg	missense_variant	4/11		NP_001018122.1
FANCA	NM_001351830.2	c.377C>G	p.Thr126Arg	missense_variant	4/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.377C>G	p.Thr126Arg	missense_variant	4/43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000438 AC: 110 AN: 251180 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.000380 AC XY: 276 AN XY: 727168

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00838

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2024	Identified in the heterozygous state in two individuals with pancreatic cancer in the published literature, however, familial segregation was not included (PMID: 15591268, 28767289); Identified in the heterozygous state in a healthy volunteer individual (PMID: 24082139); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 34173971, 15591268, 28767289, 24082139) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCA p.Thr126Arg variant was identified in dbSNP (ID: rs139160837), ClinVar (classified as a VUS by Genetic Services Laboratory, University of Chicago and as likely benign by Invitae for Fanconi Anemia) and Cosmic (FATHMM prediction of neutral; score=0.02) but was not identified in LOVD 3.0. The variant was identified in control databases in 112 of 282582 chromosomes at a frequency of 0.000396 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: Ashkenazi Jewish in 72 of 10354 chromosomes (freq: 0.006954), European (non-Finnish) in 38 of 128992 chromosomes (freq: 0.000295) and Other in 2 of 7218 chromosomes (freq: 0.000277); it was not observed in the African, Latino, East Asian, European (Finnish) and South Asian populations. The p.T126R variant was identified in 1/44 cases of familial pancreatic cancer (freq=0.011) but was not identified in 115 controls (Rogers_2004_PMID: 15591268). The variant was also found in 1/417 patients with Fanconi anemia (freq=0.001) along with a BRCA2 mutation (c.8567A>C), however the FANCA p.T126R variant was predicted to be benign (Chandrasekharappa_2017_PMID: 28678401). The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict the loss of an unreported 3' splice site. The p.Thr126 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -

Fanconi anemia Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 20, 2020	- -

Fanconi anemia complementation group A Uncertain:2

Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0070
DANN	Benign	0.35
DEOGEN2	Benign	0.068	T;.;.;T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.58	T;T;T;T;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0061	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.51	T;T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T
Polyphen		0.035	B;.;B;.;B;B
Vest4		0.28
MVP		0.20
ClinPred		0.013	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.033
gMVP		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs139160837; hg19: chr16-89877386; COSMIC: COSV66881663; COSMIC: COSV66881663;