NM_001018113.3:c.2342A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001018113.3(FANCB):c.2342A>G(p.Glu781Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,209,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.00012 ( 0 hom. 47 hem. )

Consequence

FANCB
NM_001018113.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.245

Publications

3 publications found

Variant links:

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

FANCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10991168).

BP6

Variant X-14843805-T-C is Benign according to our data. Variant chrX-14843805-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572694.

BS2

High Hemizygotes in GnomAd4 at 3 AR,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCB	NM_001018113.3 link	c.2342A>G	p.Glu781Gly	missense_variant	Exon 10 of 10	ENST00000650831.1	NP_001018123.1	Q8NB91A0A024RBW1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1 link	c.2342A>G	p.Glu781Gly	missense_variant	Exon 10 of 10		NM_001018113.3	ENSP00000498215.1		Q8NB91

Frequencies

GnomAD3 genomes

AF:

0.0000894

AC:

AN:

111823

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000169

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000328

AC:

AN:

183026

AF XY:

0.0000148

show subpopulations

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:

0.0000735

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

128

AN:

1097509

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

362901

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26390

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54131

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40409

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000147

AC:

124

AN:

841589

Other (OTH)

AF:

0.0000651

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000894

AC:

AN:

111823

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

34007

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30758

American (AMR)

AF:

0.00

AC:

AN:

10490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53188

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia

Benign:2

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Uncertain:1

Nov 30, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change does not appear to have been previously described in patients with FANCB-related disorders and has been described in the gnomAD database with a low population frequency of 0.0034% (dbSNP rs140363445). The p.Glu781Gly change affects a poorly conserved amino acid residue located in a domain of the FANCB protein that is not known to be functional. The p.Glu781Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu781Gly change remains unknown at this time. -

not provided

Uncertain:1

Dec 03, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30404791, 29654263, 31721781) -

Fanconi anemia complementation group B

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Multiple congenital anomalies/dysmorphic syndrome

Benign:1

Jan 14, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

VACTERL association, X-linked, with or without hydrocephalus

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.46

T;T;T

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.37

T;.;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M;.

PhyloP100

0.24

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.038

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.010

B;B;.

Vest4

0.082

MVP

0.16

MPC

0.13

ClinPred

0.092

GERP RS

-1.5

Varity_R

0.072

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over