chr5-83209037-C-T

Variant names:

• chr5-83209037-C-T
• rs10514249
• NM_003401.5:c.745+4116C>T

Variant summary

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

The NM_003401.5(XRCC4):​c.745+4116C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 150,928 control chromosomes in the GnomAD database, including 25,468 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 0.58 (25468 hom., cov: 29)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.299

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.745+4116C>T		intron_variant	Intron 6 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.745+4116C>T		intron_variant	Intron 6 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87156 AN: 150810 Hom.: 25425 Cov.: 29

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.568

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

GnomAD4 genome AF: 0.578 AC: 87248 AN: 150928 Hom.: 25468 Cov.: 29 AF XY: 0.573 AC XY: 42205 AN XY: 73594

African (AFR) AF: 0.672 AC: 27616 AN: 41116

American (AMR) AF: 0.539 AC: 8165 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2252 AN: 3464

East Asian (EAS) AF: 0.486 AC: 2483 AN: 5110

South Asian (SAS) AF: 0.557 AC: 2667 AN: 4788

European-Finnish (FIN) AF: 0.487 AC: 5011 AN: 10288

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37219 AN: 67722

Other (OTH) AF: 0.573 AC: 1201 AN: 2096

Alfa AF: 0.563 Hom.: 92304

Bravo AF: 0.587

Asia WGS AF: 0.593 AC: 2064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	6.4
DANN	Benign	0.25
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

Publications

LitVar

Other links and lift over

dbSNP: rs10514249; hg19: chr5-82504856; COSMIC: COSV56534819;