rs149775657

chr16-89739285-G-Achr16-89739285-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000135.4(FANCA):c.4015C>T(p.Leu1339Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L1339P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 1.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118608594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.4015C>T	p.Leu1339Phe	missense_variant	41/43	ENST00000389301.8
ZNF276	NM_001113525.2	c.*1039G>A		3_prime_UTR_variant	11/11	ENST00000443381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.4015C>T	p.Leu1339Phe	missense_variant	41/43	1	NM_000135.4	P1
ZNF276	ENST00000443381.7	c.*1039G>A		3_prime_UTR_variant	11/11	1	NM_001113525.2	P2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251296 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135872

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461776 Hom.: 0 Cov.: 35 AF XY: 0.0000440 AC XY: 32 AN XY: 727184

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74498

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group A Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 26, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 31, 2019	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 12, 2023	The frequency of this variant in the general population, 0.00028 (7/24954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported only in a healthy individual (PMID: 24728327 (2014)) and as a somatic variant in an individual with prostate cancer (PMID: 31698007 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 13, 2022	- -

Fanconi anemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.011
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.2	N;N;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.50
MVP		0.95
ClinPred		0.14	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs149775657; hg19: chr16-89805693; COSMIC: COSV57067532; COSMIC: COSV57067532;