chr5-83359290-C-T

Variant names:

• chr5-83359290-C-T
• rs9293337
• XM_017009827.3:c.894-10977C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_017009827.3(XRCC4):​c.894-10977C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 151,968 control chromosomes in the GnomAD database, including 7,523 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (7523 hom., cov: 32)
• Consequence: XRCC4 XM_017009827.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.403
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

 

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39160 AN: 151850 Hom.: 7485 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.258 AC: 39244 AN: 151968 Hom.: 7523 Cov.: 32 AF XY: 0.262 AC XY: 19428 AN XY: 74286

African (AFR) AF: 0.480 AC: 19882 AN: 41438

American (AMR) AF: 0.313 AC: 4778 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 442 AN: 3466

East Asian (EAS) AF: 0.681 AC: 3511 AN: 5152

South Asian (SAS) AF: 0.175 AC: 843 AN: 4812

European-Finnish (FIN) AF: 0.161 AC: 1707 AN: 10594

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.110 AC: 7471 AN: 67944

Other (OTH) AF: 0.240 AC: 506 AN: 2110

Alfa AF: 0.189 Hom.: 554

Bravo AF: 0.286

Asia WGS AF: 0.402 AC: 1397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.33
PhyloP100		-0.40

Splicing

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

Other links and lift over

dbSNP: rs9293337; hg19: chr5-82655109; COSMIC: COSV60160626;