chrX-14850514-G-C

Variant names:

• chrX-14850514-G-C
• rs993307430
• NM_001018113.3:c.1487C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001018113.3(FANCB):​c.1487C>G​(p.Ser496Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,087,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. S496F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.62
• Publications: 0 publications found

Genes affected

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• VACTERL association, X-linked, with or without hydrocephalus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• VACTERL with hydrocephalus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3279592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCB	NM_001018113.3	c.1487C>G	p.Ser496Cys	missense_variant	Exon 7 of 10	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1	c.1487C>G	p.Ser496Cys	missense_variant	Exon 7 of 10		NM_001018113.3	ENSP00000498215.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1087126 Hom.: 0 Cov.: 28 AF XY: 0.00000283 AC XY: 1 AN XY: 353580

African (AFR) AF: 0.00 AC: 0 AN: 26200

American (AMR) AF: 0.00 AC: 0 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19310

East Asian (EAS) AF: 0.00 AC: 0 AN: 30108

South Asian (SAS) AF: 0.00 AC: 0 AN: 53889

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4039

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 832193

Other (OTH) AF: 0.0000657 AC: 3 AN: 45694

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:1

Jun 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FANCB-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 496 of the FANCB protein (p.Ser496Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. -

Fanconi anemia complementation group B;C2931228:VACTERL association, X-linked, with or without hydrocephalus Uncertain:1

Nov 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.6	M;M;.
PhyloP100		4.6
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.31
MutPred		0.38		Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);
MVP		0.45
MPC		0.50
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.41
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs993307430; hg19: chrX-14868636;