chr16-89739526-C-G

Variant names:

• chr16-89739526-C-G
• rs374649848
• NM_000135.4:c.3962G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000135.4(FANCA):​c.3962G>C​(p.Arg1321Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,998 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1321C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.796

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000135.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28549075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.3962G>C	p.Arg1321Pro	missense_variant	Exon 40 of 43	ENST00000389301.8	NP_000126.2
ZNF276	NM_001113525.2	c.*1280C>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000443381.7	NP_001106997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.3962G>C	p.Arg1321Pro	missense_variant	Exon 40 of 43	1	NM_000135.4	ENSP00000373952.3
ZNF276	ENST00000443381.7	c.*1280C>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_001113525.2	ENSP00000415836.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000643 AC: 1 AN: 155550 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398998 Hom.: 0 Cov.: 33 AF XY: 0.00000435 AC XY: 3 AN XY: 690046

African (AFR) AF: 0.00 AC: 0 AN: 31602

American (AMR) AF: 0.00 AC: 0 AN: 35710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35748

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79244

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079024

Other (OTH) AF: 0.00 AC: 0 AN: 58004

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:2

Jul 21, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 998617). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1321 of the FANCA protein (p.Arg1321Pro). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FANCA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Jan 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1321P variant (also known as c.3962G>C), located in coding exon 40 of the FANCA gene, results from a G to C substitution at nucleotide position 3962. The arginine at codon 1321 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	6.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M;M;.
PhyloP100		-0.80
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.065	T;D;T
Sift4G	Benign	0.083	T;T;D
Polyphen		0.99	D;.;.
Vest4		0.30
MutPred		0.37		Gain of relative solvent accessibility (P = 0.0507);Gain of relative solvent accessibility (P = 0.0507);.;
MVP		0.93
ClinPred		0.47	T
GERP RS		1.8
Varity_R		0.50
gMVP		0.47
Mutation Taster		=86/14	polymorphism

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

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Other links and lift over

dbSNP: rs374649848; hg19: chr16-89805934;