rs199510538

chrX-14850507-C-AchrX-14850507-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/18 in silico tools predict a benign outcome for this variant. 2/2 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:1 B:9
• Conservation: PhyloP100: 0.0720

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]

ACMG classification

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=6, 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. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 41 XL gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 72 AN: 111815 Hom.: 1 Cov.: 23 AF XY: 0.00121 AC XY: 41 AN XY: 33997

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.: 2 AF XY: 0.00410 AC XY: 278 AN XY: 67846

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.: 14 Cov.: 27 AF XY: 0.00209 AC XY: 736 AN XY: 351375

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: 73 AN: 111866 Hom.: 1 Cov.: 23 AF XY: 0.00123 AC XY: 42 AN XY: 34058

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.: 0

Bravo AF: 0.000132

ExAC AF: 0.00320 AC: 389

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

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	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 26, 2020	- -

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. -

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	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	11
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.54	T;.;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs199510538; hg19: chrX-14868629;