X-14853048-A-C

Variant names:

• chrX-14853048-A-C
• rs776802337
• NM_001018113.3:c.1317T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001018113.3(FANCB):​c.1317T>G​(p.Ser439Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,086,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S439S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18855333).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	NM_001018113.3	MANE Select	c.1317T>G	p.Ser439Arg	missense	Exon 6 of 10	NP_001018123.1
	FANCB	NM_001410764.1		c.1317T>G	p.Ser439Arg	missense	Exon 6 of 13	NP_001397693.1
	FANCB	NM_001324162.2		c.1317T>G	p.Ser439Arg	missense	Exon 6 of 10	NP_001311091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	ENST00000650831.1	MANE Select	c.1317T>G	p.Ser439Arg	missense	Exon 6 of 10	ENSP00000498215.1
	FANCB	ENST00000324138.7	TSL:1	c.1317T>G	p.Ser439Arg	missense	Exon 5 of 9	ENSP00000326819.3
	FANCB	ENST00000452869.2	TSL:1	c.1317T>G	p.Ser439Arg	missense	Exon 6 of 11	ENSP00000397849.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 181994 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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086399 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 352903

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26180

American (AMR) AF: 0.00 AC: 0 AN: 35102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19249

East Asian (EAS) AF: 0.00 AC: 0 AN: 29966

South Asian (SAS) AF: 0.00 AC: 0 AN: 53565

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3935

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832315

Other (OTH) AF: 0.00 AC: 0 AN: 45667

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.7
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.16
Sift	Benign	0.040	D
Sift4G	Uncertain	0.034	D
Polyphen		0.92	P
Vest4		0.19
MutPred		0.20		Gain of solvent accessibility (P = 0.0367)
MVP		0.33
MPC		0.41
ClinPred		0.59	D
GERP RS		5.7
Varity_R		0.36
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs776802337; hg19: chrX-14871170;