rs1611026

Variant names:

• chr5-83249721-T-TAATC
• rs1611026
• NM_003401.5:c.746-8807_746-8804dupATCA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003401.5(XRCC4):​c.746-8807_746-8804dupATCA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (14116 hom., cov: 0)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695
• Publications: 2 publications found

Genes affected

XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

XRCC4 Gene-Disease associations (from GenCC):

• short stature, microcephaly, and endocrine dysfunction

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.746-8807_746-8804dupATCA		intron_variant	Intron 6 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.746-8809_746-8808insAATC		intron_variant	Intron 6 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57796 AN: 151376 Hom.: 14073 Cov.: 0

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.363

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.382 AC: 57904 AN: 151494 Hom.: 14116 Cov.: 0 AF XY: 0.387 AC XY: 28613 AN XY: 74010

African (AFR) AF: 0.648 AC: 26711 AN: 41250

American (AMR) AF: 0.392 AC: 5978 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 845 AN: 3472

East Asian (EAS) AF: 0.808 AC: 4118 AN: 5096

South Asian (SAS) AF: 0.312 AC: 1503 AN: 4814

European-Finnish (FIN) AF: 0.314 AC: 3293 AN: 10490

Middle Eastern (MID) AF: 0.303 AC: 88 AN: 290

European-Non Finnish (NFE) AF: 0.213 AC: 14477 AN: 67832

Other (OTH) AF: 0.370 AC: 779 AN: 2108

Alfa AF: 0.305 Hom.: 1138

Bravo AF: 0.404

Asia WGS AF: 0.533 AC: 1847 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1611026; hg19: chr5-82545540;