rs2386275

Variant names:

• chr5-83346721-G-A
• rs2386275
• NM_003401.5:c.894-6410G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-83346721-G-A
• chr5-83346721-G-C

Variant summary

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

The NM_003401.5(XRCC4):​c.894-6410G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 151,916 control chromosomes in the GnomAD database, including 7,572 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 0.26 (7572 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.403
• Publications: 3 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-6410G>A		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.894-6410G>A		intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4
XRCC4	ENST00000511817.1	c.894-6404G>A		intron_variant	Intron 7 of 7	1		ENSP00000421491.1
XRCC4	ENST00000282268.7	c.894-6410G>A		intron_variant	Intron 7 of 7	1		ENSP00000282268.3
XRCC4	ENST00000338635.10	c.894-6404G>A		intron_variant	Intron 7 of 7	2		ENSP00000342011.6

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39523 AN: 151798 Hom.: 7536 Cov.: 32

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.261 AC: 39605 AN: 151916 Hom.: 7572 Cov.: 32 AF XY: 0.266 AC XY: 19718 AN XY: 74238

African (AFR) AF: 0.473 AC: 19580 AN: 41400

American (AMR) AF: 0.315 AC: 4800 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3466

East Asian (EAS) AF: 0.707 AC: 3662 AN: 5182

South Asian (SAS) AF: 0.171 AC: 822 AN: 4816

European-Finnish (FIN) AF: 0.186 AC: 1957 AN: 10534

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7629 AN: 67954

Other (OTH) AF: 0.245 AC: 517 AN: 2112

Alfa AF: 0.202 Hom.: 637

Bravo AF: 0.286

Asia WGS AF: 0.410 AC: 1421 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.8
DANN	Benign	0.53
PhyloP100		0.40
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: rs2386275; hg19: chr5-82642540; COSMIC: COSV56535152;