rs1011980

Variant names:

• chr5-83097730-A-G
• rs1011980
• NM_003401.5:c.-10-7180A>G

Variant summary

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

The NM_022406.5(XRCC4):​c.-10-7180A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,072 control chromosomes in the GnomAD database, including 2,979 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 0.18 (2979 hom., cov: 32)
• Consequence: XRCC4 NM_022406.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.672
• Publications: 6 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=-0.69).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022406.5. 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.-10-7180A>G		intron	N/A	NP_003392.1
	XRCC4	NM_001318012.3		c.-10-7180A>G		intron	N/A	NP_001304941.1
	XRCC4	NM_022406.5		c.-10-7180A>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.-10-7180A>G		intron	N/A	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.-10-7180A>G		intron	N/A	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.-10-7180A>G		intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27020 AN: 151954 Hom.: 2978 Cov.: 32

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.178 AC: 27026 AN: 152072 Hom.: 2979 Cov.: 32 AF XY: 0.174 AC XY: 12939 AN XY: 74356

African (AFR) AF: 0.0502 AC: 2085 AN: 41538

American (AMR) AF: 0.192 AC: 2928 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3470

East Asian (EAS) AF: 0.0545 AC: 282 AN: 5174

South Asian (SAS) AF: 0.184 AC: 891 AN: 4830

European-Finnish (FIN) AF: 0.206 AC: 2176 AN: 10572

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17207 AN: 67902

Other (OTH) AF: 0.174 AC: 366 AN: 2108

Alfa AF: 0.231 Hom.: 3284

Bravo AF: 0.169

Asia WGS AF: 0.128 AC: 448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1011980; hg19: chr5-82393549;