chr5-83189445-T-C

Variant names:

• chr5-83189445-T-C
• rs2731861
• NM_003401.5:c.316-6325T>C

Variant summary

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

The NM_003401.5(XRCC4):​c.316-6325T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 151,972 control chromosomes in the GnomAD database, including 16,155 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 0.45 (16155 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.316-6325T>C		intron	N/A	NP_003392.1
	XRCC4	NM_001318012.3		c.316-6325T>C		intron	N/A	NP_001304941.1
	XRCC4	NM_022406.5		c.316-6325T>C		intron	N/A	NP_071801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.316-6325T>C		intron	N/A	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.316-6325T>C		intron	N/A	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.316-6325T>C		intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69043 AN: 151854 Hom.: 16142 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.455 AC: 69082 AN: 151972 Hom.: 16155 Cov.: 32 AF XY: 0.456 AC XY: 33834 AN XY: 74268

African (AFR) AF: 0.507 AC: 21029 AN: 41444

American (AMR) AF: 0.336 AC: 5129 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1362 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1061 AN: 5168

South Asian (SAS) AF: 0.522 AC: 2508 AN: 4808

European-Finnish (FIN) AF: 0.487 AC: 5131 AN: 10528

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31341 AN: 67966

Other (OTH) AF: 0.439 AC: 927 AN: 2114

Alfa AF: 0.292 Hom.: 562

Bravo AF: 0.473

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.94
DANN	Benign	0.71
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2731861; hg19: chr5-82485264; COSMIC: COSV56534044;