rs11951257

Variant names:

• chr5-83107492-T-C
• rs11951257
• NM_003401.5:c.139+2434T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_003401.5(XRCC4):​c.139+2434T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 151,552 control chromosomes in the GnomAD database, including 18,723 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 0.49 (18723 hom., cov: 31)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.139+2434T>C		intron	N/A	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.139+2434T>C		intron	N/A	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.139+2434T>C		intron	N/A	NP_071801.1	Q13426-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.139+2434T>C		intron	N/A	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.139+2434T>C		intron	N/A	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.139+2434T>C		intron	N/A	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73653 AN: 151434 Hom.: 18701 Cov.: 31

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.454

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

GnomAD4 genome AF: 0.486 AC: 73708 AN: 151552 Hom.: 18723 Cov.: 31 AF XY: 0.484 AC XY: 35857 AN XY: 74070

African (AFR) AF: 0.619 AC: 25611 AN: 41372

American (AMR) AF: 0.345 AC: 5258 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1331 AN: 3458

East Asian (EAS) AF: 0.189 AC: 978 AN: 5168

South Asian (SAS) AF: 0.510 AC: 2457 AN: 4814

European-Finnish (FIN) AF: 0.494 AC: 5195 AN: 10526

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.463 AC: 31328 AN: 67660

Other (OTH) AF: 0.453 AC: 955 AN: 2108

Alfa AF: 0.479 Hom.: 2195

Bravo AF: 0.475

Asia WGS AF: 0.370 AC: 1284 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.75
PhyloP100		1.1
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: rs11951257; hg19: chr5-82403311;