rs6864054

Positions:

• chr5-83078344-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.-11+729A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0622 in 152,336 control chromosomes in the GnomAD database, including 338 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 0.062 (338 hom., cov: 33)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.581

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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.-11+729A>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.-11+729A>G		intron_variant		5	NM_003401.5	ENSP00000379344	A1

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9472 AN: 152218 Hom.: 339 Cov.: 33

Gnomad AFR AF: 0.0799

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0759

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0507

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

GnomAD4 genome AF: 0.0622 AC: 9468 AN: 152336 Hom.: 338 Cov.: 33 AF XY: 0.0636 AC XY: 4735 AN XY: 74500

Gnomad4 AFR AF: 0.0796

Gnomad4 AMR AF: 0.0442

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.0761

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0506

Alfa AF: 0.0502 Hom.: 222

Bravo AF: 0.0582

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.35

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: rs6864054; hg19: chr5-82374163;