rs41309679

Positions:

• chrX-14859282-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018113.3(FANCB):​c.1004G>A​(p.Gly335Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0731 in 1,187,007 control chromosomes in the GnomAD database, including 2,526 homozygotes. There are 27,854 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (155 hom., 1766 hem., cov: 23)
  • Exomes 𝑓: 0.075 (2371 hom. 26088 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026280582).
• BP6: Variant X-14859282-C-T is Benign according to our data. Variant chrX-14859282-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCB	NM_001018113.3	c.1004G>A	p.Gly335Glu	missense_variant	4/10	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1	c.1004G>A	p.Gly335Glu	missense_variant	4/10		NM_001018113.3	ENSP00000498215	P2

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 6078 AN: 111377 Hom.: 156 Cov.: 23 AF XY: 0.0526 AC XY: 1769 AN XY: 33625

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00872

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000561

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0684

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.0674

GnomAD3 exomes AF: 0.0617 AC: 11246 AN: 182122 Hom.: 311 AF XY: 0.0656 AC XY: 4379 AN XY: 66726

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.0896

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0720

Gnomad FIN exome AF: 0.0775

Gnomad NFE exome AF: 0.0843

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0750 AC: 80647 AN: 1075579 Hom.: 2371 Cov.: 25 AF XY: 0.0758 AC XY: 26088 AN XY: 344073

Gnomad4 AFR exome AF: 0.00980

Gnomad4 AMR exome AF: 0.0287

Gnomad4 ASJ exome AF: 0.0928

Gnomad4 EAS exome AF: 0.000434

Gnomad4 SAS exome AF: 0.0782

Gnomad4 FIN exome AF: 0.0808

Gnomad4 NFE exome AF: 0.0812

Gnomad4 OTH exome AF: 0.0681

GnomAD4 genome AF: 0.0545 AC: 6072 AN: 111428 Hom.: 155 Cov.: 23 AF XY: 0.0524 AC XY: 1766 AN XY: 33686

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.000563

Gnomad4 SAS AF: 0.0615

Gnomad4 FIN AF: 0.0763

Gnomad4 NFE AF: 0.0816

Gnomad4 OTH AF: 0.0665

Alfa AF: 0.0797 Hom.: 3987

Bravo AF: 0.0510

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0723 AC: 209

ESP6500AA AF: 0.0149 AC: 57

ESP6500EA AF: 0.0842 AC: 566

ExAC AF: 0.0663 AC: 8054

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia complementation group B Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	This variant is associated with the following publications: (PMID: 30679340) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

VACTERL association, X-linked, with or without hydrocephalus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T;.;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	2.9	M;M;.
MutationTaster	Benign	0.056	P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.22
MPC		0.58
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs41309679; hg19: chrX-14877404; COSMIC: COSV60758740;