X-14843534-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 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

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 -14 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 id is 368019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000991 (111/112007) while in subpopulation NFE AF= 0.00154 (82/53173). AF 95% confidence interval is 0.00127. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCB	NM_001018113.3	c.*33T>C		3_prime_UTR_variant	10/10	ENST00000650831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCB	ENST00000650831.1	c.*33T>C		3_prime_UTR_variant	10/10		NM_001018113.3	P2

Frequencies

GnomAD3 genomes AF: 0.000991 AC: 111 AN: 111954 Hom.: 0 Cov.: 22 AF XY: 0.000821 AC XY: 28 AN XY: 34100

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

GnomAD3 exomes AF: 0.00176 AC: 260 AN: 147602 Hom.: 3 AF XY: 0.00160 AC XY: 74 AN XY: 46384

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 SAS 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

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.000677

Gnomad4 EAS exome AF: 0.0000355

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000747

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00166

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

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.00133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00133

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00

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

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. -

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
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.29
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs187611308; hg19: chrX-14861656;