rs2905223

Positions:

• chrX-14850684-A-G
• chrX-14850684-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001018113.3(FANCB):​c.1327-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (11742 hom., 16080 hem., cov: 21)
  • Exomes 𝑓: 0.58 (120219 hom. 169168 hem.)
  • Failed GnomAD Quality Control
• Consequence: FANCB NM_001018113.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002456
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.27

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-14850684-A-G is Benign according to our data. Variant chrX-14850684-A-G is described in ClinVar as [Benign]. Clinvar id is 93467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-14850684-A-G is described in Lovd as [Benign]. Variant chrX-14850684-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCB	NM_001018113.3	c.1327-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1	c.1327-10T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_001018113.3	ENSP00000498215	P2

Frequencies

GnomAD3 genomes AF: 0.535 AC: 58196 AN: 108757 Hom.: 11746 Cov.: 21 AF XY: 0.514 AC XY: 16063 AN XY: 31235

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.869

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.534

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.507

GnomAD3 exomes AF: 0.517 AC: 78766 AN: 152467 Hom.: 15122 AF XY: 0.516 AC XY: 23447 AN XY: 45399

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.555

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.611

Gnomad NFE exome AF: 0.610

Gnomad OTH exome AF: 0.545

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.576 AC: 573309 AN: 995768 Hom.: 120219 Cov.: 18 AF XY: 0.574 AC XY: 169168 AN XY: 294908

Gnomad4 AFR exome AF: 0.478

Gnomad4 AMR exome AF: 0.447

Gnomad4 ASJ exome AF: 0.560

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.610

Gnomad4 OTH exome AF: 0.558

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.535 AC: 58192 AN: 108802 Hom.: 11742 Cov.: 21 AF XY: 0.514 AC XY: 16080 AN XY: 31290

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.479

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.584

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.498

Alfa AF: 0.579 Hom.: 9715

Bravo AF: 0.527

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2013	- -

Fanconi anemia complementation group B Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Aug 10, 2021	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	- -

VACTERL association, X-linked, with or without hydrocephalus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

X-linked central congenital hypothyroidism with late-onset testicular enlargement Benign:1

Likely benign, no assertion criteria provided

curation

Leiden Open Variation Database

Feb 28, 2020

Curator: Arleen D. Auerbach. Submitter to LOVD: Yu Sun. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2905223; hg19: chrX-14868806; COSMIC: COSV60762278;