rs301286

Variant names:

• chr5-83307136-C-T
• rs301286
• NM_003401.5:c.894-45995C>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.894-45995C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,080 control chromosomes in the GnomAD database, including 35,591 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 0.65 (35591 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 7 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-45995C>T		intron_variant	Intron 7 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.894-45995C>T		intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98358 AN: 151962 Hom.: 35584 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.647 AC: 98396 AN: 152080 Hom.: 35591 Cov.: 32 AF XY: 0.641 AC XY: 47666 AN XY: 74334

African (AFR) AF: 0.334 AC: 13859 AN: 41458

American (AMR) AF: 0.651 AC: 9948 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2978 AN: 3470

East Asian (EAS) AF: 0.297 AC: 1532 AN: 5164

South Asian (SAS) AF: 0.721 AC: 3480 AN: 4828

European-Finnish (FIN) AF: 0.712 AC: 7511 AN: 10552

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56603 AN: 67994

Other (OTH) AF: 0.686 AC: 1452 AN: 2116

Alfa AF: 0.759 Hom.: 68228

Bravo AF: 0.624

Asia WGS AF: 0.567 AC: 1976 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.67
DANN	Benign	0.38
PhyloP100		-0.58
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: rs301286; hg19: chr5-82602955; COSMIC: COSV56534942;