chrX-14843534-A-G

Variant names:

• chrX-14843534-A-G
• rs187611308
• NM_001018113.3:c.*33T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001018113.3(FANCB):​c.*33T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,067,493 control chromosomes in the GnomAD database, including 5 homozygotes. There are 447 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., 28 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (5 hom. 419 hem.)
• Consequence: FANCB NM_001018113.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.264
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• VACTERL association, X-linked, with or without hydrocephalus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• VACTERL with hydrocephalus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-14843534-A-G is Benign according to our data. Variant chrX-14843534-A-G is described in ClinVar as Benign. ClinVar VariationId is 368019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 28 AR,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCB	NM_001018113.3	c.*33T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1	c.*33T>C		3_prime_UTR_variant	Exon 10 of 10		NM_001018113.3	ENSP00000498215.1

Frequencies

GnomAD3 genomes AF: 0.000991 AC: 111 AN: 111954 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00176 AC: 260 AN: 147602 AF XY: 0.00160

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.00386

Gnomad ASJ exome AF: 0.000670

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000874

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00789

GnomAD4 exome AF: 0.00162 AC: 1545 AN: 955486 Hom.: 5 Cov.: 16 AF XY: 0.00154 AC XY: 419 AN XY: 272366

African (AFR) AF: 0.0000898 AC: 2 AN: 22280

American (AMR) AF: 0.00416 AC: 132 AN: 31699

Ashkenazi Jewish (ASJ) AF: 0.000677 AC: 12 AN: 17723

East Asian (EAS) AF: 0.0000355 AC: 1 AN: 28160

South Asian (SAS) AF: 0.00 AC: 0 AN: 46861

European-Finnish (FIN) AF: 0.000747 AC: 29 AN: 38813

Middle Eastern (MID) AF: 0.000323 AC: 1 AN: 3099

European-Non Finnish (NFE) AF: 0.00179 AC: 1300 AN: 725911

Other (OTH) AF: 0.00166 AC: 68 AN: 40940

GnomAD4 genome AF: 0.000991 AC: 111 AN: 112007 Hom.: 0 Cov.: 22 AF XY: 0.000820 AC XY: 28 AN XY: 34163

African (AFR) AF: 0.000227 AC: 7 AN: 30896

American (AMR) AF: 0.00133 AC: 14 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2733

European-Finnish (FIN) AF: 0.00133 AC: 8 AN: 6029

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00154 AC: 82 AN: 53173

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.000523 Hom.: 2

Bravo AF: 0.00112

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group B Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.29
DANN	Benign	0.54
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs187611308; hg19: chrX-14861656;