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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	XM_017009827.3	c.894-10977C>T		intron_variant	Intron 7 of 8		XP_016865316.1
XRCC4	XM_047417695.1	c.894-10977C>T		intron_variant	Intron 7 of 8		XP_047273651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

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 v4.3

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;