chr5-83078344-A-G

Variant names:

• chr5-83078344-A-G
• rs6864054
• NM_003401.5:c.-11+729A>G

Variant summary

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

The ENST00000396027.9(XRCC4):​c.-11+729A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0622 in 152,336 control chromosomes in the GnomAD database, including 338 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 0.062 (338 hom., cov: 33)
• Consequence: XRCC4 ENST00000396027.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.581
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396027.9. 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.-11+729A>G		intron	N/A	NP_003392.1
	XRCC4	NM_001318012.3		c.-11+682A>G		intron	N/A	NP_001304941.1
	XRCC4	NM_022406.5		c.-11+729A>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.-11+729A>G		intron	N/A	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.-11+682A>G		intron	N/A	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.-11+682A>G		intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9472 AN: 152218 Hom.: 339 Cov.: 33

Gnomad AFR AF: 0.0799

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0759

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0507

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

GnomAD4 genome AF: 0.0622 AC: 9468 AN: 152336 Hom.: 338 Cov.: 33 AF XY: 0.0636 AC XY: 4735 AN XY: 74500

African (AFR) AF: 0.0796 AC: 3307 AN: 41566

American (AMR) AF: 0.0442 AC: 677 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.0761 AC: 395 AN: 5190

South Asian (SAS) AF: 0.172 AC: 829 AN: 4826

European-Finnish (FIN) AF: 0.0651 AC: 692 AN: 10624

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0481 AC: 3271 AN: 68030

Other (OTH) AF: 0.0506 AC: 107 AN: 2114

Alfa AF: 0.0513 Hom.: 292

Bravo AF: 0.0582

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.35
PhyloP100		-0.58
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: rs6864054; hg19: chr5-82374163;