rs13178127

Variant names:

• chr5-83293613-A-G
• rs13178127
• NM_003401.5:c.893+34936A>G

Variant summary

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

The NM_003401.5(XRCC4):​c.893+34936A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 152,066 control chromosomes in the GnomAD database, including 143 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 0.033 (143 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.714
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0518 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.893+34936A>G		intron	N/A	NP_003392.1
	XRCC4	NM_001318012.3		c.893+34936A>G		intron	N/A	NP_001304941.1
	XRCC4	NM_022406.5		c.893+34936A>G		intron	N/A	NP_071801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.893+34936A>G		intron	N/A	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.893+34936A>G		intron	N/A	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.893+34936A>G		intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4990 AN: 151948 Hom.: 144 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0245

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

GnomAD4 genome AF: 0.0328 AC: 4988 AN: 152066 Hom.: 143 Cov.: 32 AF XY: 0.0306 AC XY: 2272 AN XY: 74344

African (AFR) AF: 0.0109 AC: 453 AN: 41518

American (AMR) AF: 0.0242 AC: 369 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4828

European-Finnish (FIN) AF: 0.0252 AC: 267 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0532 AC: 3616 AN: 67916

Other (OTH) AF: 0.0242 AC: 51 AN: 2106

Alfa AF: 0.0394 Hom.: 151

Bravo AF: 0.0313

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.32
PhyloP100		0.71
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: rs13178127; hg19: chr5-82589432;