rs993307430

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-14850514-G-A
• chrX-14850514-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_001018113.3(FANCB):​c.1487C>T​(p.Ser496Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000184 in 1,087,125 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. S496C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.388739).
• BS2: High Hemizygotes in GnomAdExome4 at 2 AR,XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCB	NM_001018113.3	c.1487C>T	p.Ser496Phe	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>T	p.Ser496Phe	missense_variant	Exon 7 of 10		NM_001018113.3	ENSP00000498215.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1087125 Hom.: 0 Cov.: 28 AF XY: 0.00000566 AC XY: 2 AN XY: 353579

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: 0.0000186 AC: 1 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: 0.00000120 AC: 1 AN: 832192

Other (OTH) AF: 0.00 AC: 0 AN: 45694

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with phenylalanine at codon 496 of the FANCB protein (p.Ser496Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCB-related conditions. 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"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.6	M;M;.
PhyloP100		4.6
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.054	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.29
MutPred		0.37		Loss of disorder (P = 0.0077);Loss of disorder (P = 0.0077);Loss of disorder (P = 0.0077);
MVP		0.36
MPC		0.53
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.65
Mutation Taster		=80/20	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;