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rs149695930

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001018113.3(FANCB):​c.1371C>T​(p.Val457=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,188,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 127 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).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 6 hem., cov: 22)
Exomes 𝑓: 0.00037 ( 0 hom. 121 hem. )

Consequence

FANCB
NM_001018113.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.118
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 -14 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-14850630-G-A is Benign according to our data. Variant chrX-14850630-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198442.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.118 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0003 (33/109925) while in subpopulation NFE AF= 0.000493 (26/52740). AF 95% confidence interval is 0.000345. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCBNM_001018113.3 linkuse as main transcriptc.1371C>T p.Val457= synonymous_variant 7/10 ENST00000650831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCBENST00000650831.1 linkuse as main transcriptc.1371C>T p.Val457= synonymous_variant 7/10 NM_001018113.3 P2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000300
AC:
33
AN:
109875
Hom.:
0
Cov.:
22
AF XY:
0.000186
AC XY:
6
AN XY:
32243
show subpopulations
Gnomad AFR
AF:
0.000133
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000195
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000179
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000493
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000394
AC:
71
AN:
180421
Hom.:
0
AF XY:
0.000322
AC XY:
21
AN XY:
65121
show subpopulations
Gnomad AFR exome
AF:
0.0000771
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000189
Gnomad NFE exome
AF:
0.000832
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000370
AC:
399
AN:
1078076
Hom.:
0
Cov.:
26
AF XY:
0.000350
AC XY:
121
AN XY:
345950
show subpopulations
Gnomad4 AFR exome
AF:
0.0000384
Gnomad4 AMR exome
AF:
0.0000286
Gnomad4 ASJ exome
AF:
0.0000521
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000223
Gnomad4 NFE exome
AF:
0.000444
Gnomad4 OTH exome
AF:
0.000462
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000300
AC:
33
AN:
109925
Hom.:
0
Cov.:
22
AF XY:
0.000186
AC XY:
6
AN XY:
32303
show subpopulations
Gnomad4 AFR
AF:
0.000133
Gnomad4 AMR
AF:
0.000195
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000179
Gnomad4 NFE
AF:
0.000493
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000356
Hom.:
2
Bravo
AF:
0.000314

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 03, 2014- -
Fanconi anemia Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Mar 14, 2022- -
Fanconi anemia complementation group B Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
VACTERL association, X-linked, with or without hydrocephalus Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.84
DANN
Benign
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs149695930; hg19: chrX-14868752; API