chr5-83097869-A-G

Variant names:

• chr5-83097869-A-G
• rs1011981
• NM_003401.5:c.-10-7041A>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.-10-7041A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 151,892 control chromosomes in the GnomAD database, including 13,557 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 0.41 (13557 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57
• Publications: 7 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.-10-7041A>G		intron_variant	Intron 1 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.-10-7041A>G		intron_variant	Intron 1 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62905 AN: 151774 Hom.: 13549 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.397

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

GnomAD4 genome AF: 0.414 AC: 62942 AN: 151892 Hom.: 13557 Cov.: 32 AF XY: 0.412 AC XY: 30561 AN XY: 74192

African (AFR) AF: 0.489 AC: 20249 AN: 41448

American (AMR) AF: 0.298 AC: 4543 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3464

East Asian (EAS) AF: 0.111 AC: 574 AN: 5168

South Asian (SAS) AF: 0.365 AC: 1758 AN: 4822

European-Finnish (FIN) AF: 0.437 AC: 4600 AN: 10534

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.423 AC: 28711 AN: 67888

Other (OTH) AF: 0.394 AC: 829 AN: 2106

Alfa AF: 0.413 Hom.: 6954

Bravo AF: 0.403

Asia WGS AF: 0.239 AC: 831 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		3.6
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: rs1011981; hg19: chr5-82393688;