rs13178127

Positions:

• chr5-83293613-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003401.5(XRCC4):​c.893+34936A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 152,066 control chromosomes in the GnomAD database, including 143 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 0.033 (143 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.714

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.893+34936A>G		intron_variant		ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.893+34936A>G		intron_variant		5	NM_003401.5	ENSP00000379344	A1

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4990 AN: 151948 Hom.: 144 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0245

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

GnomAD4 genome AF: 0.0328 AC: 4988 AN: 152066 Hom.: 143 Cov.: 32 AF XY: 0.0306 AC XY: 2272 AN XY: 74344

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.0289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0532

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0449 Hom.: 103

Bravo AF: 0.0313

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.32

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: rs13178127; hg19: chr5-82589432;