rs41309679

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G335R) has been classified as Uncertain significance.

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.56

Publications

16 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 -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
FANCB	NM_001018113.3 link	c.1004G>A	p.Gly335Glu	missense_variant	Exon 4 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.1004G>A	p.Gly335Glu	missense_variant	Exon 4 of 10		NM_001018113.3	ENSP00000498215.1		Q8NB91

Frequencies

GnomAD3 genomes

AF:

0.0546

AC:

6078

AN:

111377

Hom.:

156

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0617

AC:

11246

AN:

182122

AF XY:

0.0656

show subpopulations

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 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.:

AF XY:

0.0758

AC XY:

26088

AN XY:

344073

show subpopulations

African (AFR)

AF:

0.00980

AC:

255

AN:

26011

American (AMR)

AF:

0.0287

AC:

1007

AN:

35095

Ashkenazi Jewish (ASJ)

AF:

0.0928

AC:

1781

AN:

19186

East Asian (EAS)

AF:

0.000434

AC:

AN:

29980

South Asian (SAS)

AF:

0.0782

AC:

4183

AN:

53457

European-Finnish (FIN)

AF:

0.0808

AC:

3273

AN:

40491

Middle Eastern (MID)

AF:

0.0750

AC:

305

AN:

4065

European-Non Finnish (NFE)

AF:

0.0812

AC:

66743

AN:

821991

Other (OTH)

AF:

0.0681

AC:

3087

AN:

45303

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2202

4404

6607

8809

11011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2428

4856

7284

9712

12140

<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:

0.0545

AC:

6072

AN:

111428

Hom.:

155

Cov.:

AF XY:

0.0524

AC XY:

1766

AN XY:

33686

show subpopulations

African (AFR)

AF:

0.0101

AC:

312

AN:

30808

American (AMR)

AF:

0.0405

AC:

425

AN:

10484

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

276

AN:

2637

East Asian (EAS)

AF:

0.000563

AC:

AN:

3553

South Asian (SAS)

AF:

0.0615

AC:

165

AN:

2682

European-Finnish (FIN)

AF:

0.0763

AC:

448

AN:

5873

Middle Eastern (MID)

AF:

0.0563

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.0816

AC:

4325

AN:

52972

Other (OTH)

AF:

0.0665

AC:

101

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0760

Hom.:

4039

Bravo

AF:

0.0510

TwinsUK

AF:

0.0863

AC:

320

ALSPAC

AF:

0.0723

AC:

209

ESP6500AA

AF:

0.0149

AC:

ESP6500EA

AF:

0.0842

AC:

566

ExAC

AF:

0.0663

AC:

8054

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group B

Benign:4

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30679340) -

Inborn genetic diseases

Benign:1

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;D;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

T;.;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Pathogenic

2.9

M;M;.

PhyloP100

4.6

PrimateAI

Uncertain

0.51

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

GERP RS

5.8

Varity_R

0.85

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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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