rs301287

Variant names:

• chr5-83309391-A-G
• rs301287
• NM_003401.5:c.894-43740A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-83309391-A-G
• chr5-83309391-A-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.894-43740A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 146,970 control chromosomes in the GnomAD database, including 43,981 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 0.76 (43981 hom., cov: 23)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• Publications: 9 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-43740A>G		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.894-43740A>G		intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.761 AC: 111843 AN: 146908 Hom.: 43977 Cov.: 23

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.809

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

GnomAD4 genome AF: 0.761 AC: 111864 AN: 146970 Hom.: 43981 Cov.: 23 AF XY: 0.760 AC XY: 54249 AN XY: 71420

African (AFR) AF: 0.537 AC: 21338 AN: 39748

American (AMR) AF: 0.837 AC: 12255 AN: 14644

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3084 AN: 3452

East Asian (EAS) AF: 0.795 AC: 3832 AN: 4820

South Asian (SAS) AF: 0.773 AC: 3612 AN: 4672

European-Finnish (FIN) AF: 0.783 AC: 7192 AN: 9184

Middle Eastern (MID) AF: 0.818 AC: 229 AN: 280

European-Non Finnish (NFE) AF: 0.861 AC: 57894 AN: 67244

Other (OTH) AF: 0.807 AC: 1631 AN: 2020

Alfa AF: 0.832 Hom.: 23257

Bravo AF: 0.750

Asia WGS AF: 0.757 AC: 2629 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.4
DANN	Benign	0.79
PhyloP100		0.039
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: rs301287; hg19: chr5-82605210;