rs200161949

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001018113.3(FANCB):c.989T>C(p.Ile330Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000576 in 1,191,371 control chromosomes in the GnomAD database, including 1 homozygotes. There are 217 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I330I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00059 ( 1 hom. 206 hem. )

Consequence

FANCB
NM_001018113.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 5.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028166264).

BP6

Variant X-14859297-A-G is Benign according to our data. Variant chrX-14859297-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197175.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=4, Uncertain_significance=1}. Variant chrX-14859297-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000474 (53/111876) while in subpopulation AMR AF= 0.00124 (13/10516). AF 95% confidence interval is 0.000731. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCB	NM_001018113.3 linkuse as main transcript	c.989T>C	p.Ile330Thr	missense_variant	4/10	ENST00000650831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCB	ENST00000650831.1 linkuse as main transcript	c.989T>C	p.Ile330Thr	missense_variant	4/10		NM_001018113.3	P2

Frequencies

GnomAD3 genomes

AF:

0.000474

AC:

AN:

111825

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

33987

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000640

Gnomad OTH

AF:

0.00200

GnomAD3 exomes

AF:

0.000504

AC:

AN:

182720

Hom.:

AF XY:

0.000490

AC XY:

AN XY:

67286

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.000268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000490

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000586

AC:

633

AN:

1079495

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

206

AN XY:

346783

show subpopulations

Gnomad4 AFR exome

AF:

0.0000767

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.000208

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000652

Gnomad4 OTH exome

AF:

0.000704

GnomAD4 genome

AF:

0.000474

AC:

AN:

111876

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

34048

show subpopulations

Gnomad4 AFR

AF:

0.0000648

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000377

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000640

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.000514

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000453

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FANCB: BP4, BS2 -

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 20, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 16, 2021

- -

FANCB-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.020

Cadd

Benign

Dann

Benign

0.93

DEOGEN2

Uncertain

0.45

T;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

T;.;T

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

M;M;.

MutationTaster

Benign

0.96

N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.26

Sift

Benign

0.10

T;T;T

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.11

B;B;.

Vest4

0.53

MVP

0.61

MPC

0.32

ClinPred

0.032

GERP RS

5.8

Varity_R

0.27

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over