rs199510538

Positions:

Variant summary

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

The NM_001018113.3(FANCB):c.1494G>T(p.Lys498Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,196,527 control chromosomes in the GnomAD database, including 15 homozygotes. There are 778 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00065 ( 1 hom., 42 hem., cov: 23)

Exomes 𝑓: 0.0012 ( 14 hom. 736 hem. )

Consequence

FANCB
NM_001018113.3 missense, splice_region

Scores

Splicing: ADA: 0.0006412

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.0720

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=0.0028890371).

BP6

Variant X-14850507-C-A is Benign according to our data. Variant chrX-14850507-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 368024.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=1, Uncertain_significance=1}. Variant chrX-14850507-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000653 (73/111866) while in subpopulation SAS AF= 0.027 (73/2708). AF 95% confidence interval is 0.022. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 42 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCB	NM_001018113.3 linkuse as main transcript	c.1494G>T	p.Lys498Asn	missense_variant, splice_region_variant	7/10	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1 linkuse as main transcript	c.1494G>T	p.Lys498Asn	missense_variant, splice_region_variant	7/10		NM_001018113.3	ENSP00000498215	P2

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

111815

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

33997

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00252

AC:

463

AN:

183378

Hom.:

AF XY:

0.00410

AC XY:

278

AN XY:

67846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0237

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00121

AC:

1308

AN:

1084661

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

736

AN XY:

351375

show subpopulations

Gnomad4 AFR exome

AF:

0.0000765

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0231

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000482

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.000653

AC:

AN:

111866

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

34058

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0270

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.00320

AC:

389

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 26, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Fanconi anemia complementation group B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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	Jan 30, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2014

The p.K498N variant (also known as c.1494G>T), located in coding exon 5 of the FANCB gene, results from a G to T substitution at nucleotide position 1494. The lysine at codon 498 is replaced by asparagine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs199510538, but a population frequency was unavailable. This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6,500 samples with coverage at this position. This amino acid position is not conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Fanconi anemia complementation group B;C2931228:VACTERL association, X-linked, with or without hydrocephalus

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 23, 2021

- -

VACTERL association, X-linked, with or without hydrocephalus

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Benign

0.15

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;T

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.54

T;.;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.084

T;T;T

Polyphen

0.92

P;P;.

Vest4

0.049

MutPred

0.23

Loss of ubiquitination at K498 (P = 0.0174);Loss of ubiquitination at K498 (P = 0.0174);Loss of ubiquitination at K498 (P = 0.0174);

MVP

0.31

MPC

0.13

ClinPred

0.039

GERP RS

2.7

Varity_R

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00064

dbscSNV1_RF

Benign

0.054

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