X-14850676-TAAA-TAAAAAAAAA

Variant names:

• chrX-14850676-T-TAAAAAA
• rs202067682
• NM_001018113.3:c.1327-8_1327-3dupTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001018113.3(FANCB):​c.1327-8_1327-3dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 952,421 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: FANCB NM_001018113.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.476
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCB	NM_001018113.3	c.1327-8_1327-3dupTTTTTT		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1	c.1327-3_1327-2insTTTTTT		splice_region_variant, intron_variant	Intron 6 of 9		NM_001018113.3	ENSP00000498215.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 952421 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 272203

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23063

American (AMR) AF: 0.0000329 AC: 1 AN: 30354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17284

East Asian (EAS) AF: 0.00 AC: 0 AN: 26277

South Asian (SAS) AF: 0.00 AC: 0 AN: 45762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37815

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3586

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 727820

Other (OTH) AF: 0.00 AC: 0 AN: 40460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202067682; hg19: chrX-14868798;