chrX-14844672-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001018113.3(FANCB):​c.1996G>A​(p.Gly666Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,208,885 control chromosomes in the GnomAD database, including 7 homozygotes. There are 276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 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 0.0032 ( 1 hom., 103 hem., cov: 23)
Exomes 𝑓: 0.00060 ( 6 hom. 173 hem. )

Consequence

FANCB
NM_001018113.3 missense

Scores

16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.455
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0074588656).
BP6
Variant X-14844672-C-T is Benign according to our data. Variant chrX-14844672-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246612.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chrX-14844672-C-T is described in Lovd as [Likely_benign]. Variant chrX-14844672-C-T is described in Lovd as [Benign].
BS2
High Hemizygotes in GnomAd4 at 103 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCBNM_001018113.3 linkc.1996G>A p.Gly666Ser missense_variant Exon 9 of 10 ENST00000650831.1 NP_001018123.1 Q8NB91A0A024RBW1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCBENST00000650831.1 linkc.1996G>A p.Gly666Ser missense_variant Exon 9 of 10 NM_001018113.3 ENSP00000498215.1 Q8NB91

Frequencies

GnomAD3 genomes
AF:
0.00311
AC:
347
AN:
111473
Hom.:
1
Cov.:
23
AF XY:
0.00291
AC XY:
98
AN XY:
33725
show subpopulations
Gnomad AFR
AF:
0.0102
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000476
Gnomad ASJ
AF:
0.00719
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000943
Gnomad OTH
AF:
0.00334
GnomAD3 exomes
AF:
0.00116
AC:
212
AN:
183142
Hom.:
0
AF XY:
0.000856
AC XY:
58
AN XY:
67780
show subpopulations
Gnomad AFR exome
AF:
0.0109
Gnomad AMR exome
AF:
0.000255
Gnomad ASJ exome
AF:
0.00601
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.000888
GnomAD4 exome
AF:
0.000604
AC:
663
AN:
1097362
Hom.:
6
Cov.:
30
AF XY:
0.000477
AC XY:
173
AN XY:
362772
show subpopulations
Gnomad4 AFR exome
AF:
0.0124
Gnomad4 AMR exome
AF:
0.000455
Gnomad4 ASJ exome
AF:
0.00645
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000370
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000107
Gnomad4 OTH exome
AF:
0.00217
GnomAD4 genome
AF:
0.00317
AC:
353
AN:
111523
Hom.:
1
Cov.:
23
AF XY:
0.00305
AC XY:
103
AN XY:
33785
show subpopulations
Gnomad4 AFR
AF:
0.0104
Gnomad4 AMR
AF:
0.000476
Gnomad4 ASJ
AF:
0.00719
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000943
Gnomad4 OTH
AF:
0.00329
Alfa
AF:
0.000649
Hom.:
29
Bravo
AF:
0.00367
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0112
AC:
43
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.00114
AC:
139
EpiCase
AF:
0.000109
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 19, 2018- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
History of neurodevelopmental disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 16, 2013Co-segregation data for this variant is currently unavailable.This variant has not been detected in conjunction with a pathogenic mutation to date.This variant was previously reported in the SNPDatabase as rs145110602. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.25% (5/1997) total male alleles studied and but was not observed in the homozygous state out of 3381females studied. The A-allele was observed in 0.96% (5/522) African American male alleles but was absent out of 1475 European American male alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 2/1048 (0.19%) and the highest frequency was in 2/48 (4.17%) African-American SW male chromosomes studied.This amino acid position is not conserved on species alignment.This alteration is predicted to be benign with a score of 0.002 (sensitivity: 0.99; specificity: 0.17)This alteration is predicted to be tolerated with a score of 0.390 (conservation: 2.57) -
Fanconi anemia complementation group B Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Fanconi anemia Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2025- -
FANCB-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 18, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.71
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
1.9
DANN
Benign
0.40
DEOGEN2
Benign
0.062
T;T;T
FATHMM_MKL
Benign
0.027
N
LIST_S2
Benign
0.38
T;.;T
MetaRNN
Benign
0.0075
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.85
L;L;.
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-0.70
N;N;N
REVEL
Benign
0.033
Sift
Benign
0.56
T;T;T
Sift4G
Benign
0.78
T;T;T
Polyphen
0.098
B;B;.
Vest4
0.16
MVP
0.21
MPC
0.10
ClinPred
0.0017
T
GERP RS
-1.1
Varity_R
0.041

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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.

Other links and lift over

dbSNP: rs145110602; hg19: chrX-14862794; COSMIC: COSV60759880; API