16-89746670-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.3427C>G(p.Leu1143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1143P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: -1.64

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 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=0.011797249).
• BP6: Variant 16-89746670-G-C is Benign according to our data. Variant chr16-89746670-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134267.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, not_provided=1, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.3427C>G	p.Leu1143Val	missense_variant	35/43	ENST00000389301.8
FANCA	NM_001286167.3	c.3427C>G	p.Leu1143Val	missense_variant	35/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.3427C>G	p.Leu1143Val	missense_variant	35/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000525 AC: 132 AN: 251336 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135854

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000484 AC: 708 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.000495 AC XY: 360 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000518

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000459 AC: 70 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74502

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.000680

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FANCA: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Identified in the heterozygous state in individuals with breast cancer, but familial segregation information was limited and additional clinical information was not included (Seal et al., 2003; Litim et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 14695169, 23021409) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 17, 2023	- -

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 26, 2019	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 14, 2021	- -

Fanconi anemia complementation group A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 31, 2023

The FANCA c.3427C>G (p.Leu1143Val) missense change has a maximum non-founder subpopulation frequency of 0.070% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the role of this variant in Fanconi anemia. It has therefore been classified as of uncertain significance. -

FANCA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.21
Dann	Benign	0.32
DEOGEN2	Benign	0.092	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.46	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.28
Sift	Benign	0.88	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0050	B;.
Vest4		0.090
MVP		0.76
ClinPred		0.0020	T
GERP RS		-11
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.023
gMVP		0.12

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: rs61753269; hg19: chr16-89813078; COSMIC: COSV59799202; COSMIC: COSV59799202;