16-89808363-G-C

Position:

• chr16-89808363-G-C

Variant summary

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

The NM_000135.4(FANCA):​c.527C>G​(p.Ser176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.44

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 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=0.15297794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.527C>G	p.Ser176Cys	missense_variant	6/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.527C>G	p.Ser176Cys	missense_variant	6/43		NP_001273096.1
FANCA	NM_001018112.3	c.527C>G	p.Ser176Cys	missense_variant	6/11		NP_001018122.1
FANCA	NM_001351830.2	c.431C>G	p.Ser144Cys	missense_variant	5/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.527C>G	p.Ser176Cys	missense_variant	6/43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2021

This sequence change replaces serine with cysteine at codon 176 of the FANCA protein (p.Ser176Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCA-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -

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

Nov 10, 2022

The FANCA c.527C>G (p.Ser176Cys) missense change is absent 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 clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Benign	0.65
DEOGEN2	Benign	0.37	T;.;.;T;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.74	T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N;N;D;D;D;D
REVEL	Benign	0.034
Sift	Benign	0.16	T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;D;D;D;D
Polyphen		0.062	B;.;B;.;B;B
Vest4		0.39
MutPred		0.37		Gain of catalytic residue at L177 (P = 0.0101);Gain of catalytic residue at L177 (P = 0.0101);Gain of catalytic residue at L177 (P = 0.0101);Gain of catalytic residue at L177 (P = 0.0101);Gain of catalytic residue at L177 (P = 0.0101);.;
MVP		0.62
ClinPred		0.12	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.078

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: rs35566151; hg19: chr16-89874771;