rs2662238

chr5-83203488-G-Achr5-83203488-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003401.5(XRCC4):c.483-64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,313,676 control chromosomes in the GnomAD database, including 131,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13518 hom., cov: 32)
  • Exomes 𝑓: 0.44 (117628 hom.)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.172

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-83203488-G-A is Benign according to our data. Variant chr5-83203488-G-A is described in ClinVar as [Benign]. Clinvar id is 1230719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC4	NM_003401.5	c.483-64G>A		intron_variant		ENST00000396027.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC4	ENST00000396027.9	c.483-64G>A		intron_variant		5	NM_003401.5	A1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62744 AN: 151708 Hom.: 13505 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.444 AC: 515979 AN: 1161850 Hom.: 117628 AF XY: 0.448 AC XY: 257446 AN XY: 574800

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.361

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.516

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.413 AC: 62772 AN: 151826 Hom.: 13518 Cov.: 32 AF XY: 0.415 AC XY: 30802 AN XY: 74204

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.363

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.407

Alfa AF: 0.426 Hom.: 1721

Bravo AF: 0.389

Asia WGS AF: 0.358 AC: 1237 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.3
Dann	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs2662238; hg19: chr5-82499307; COSMIC: COSV56534362; COSMIC: COSV56534362;