chr5-83249564-C-G

Variant names:

• chr5-83249564-C-G
• rs6452536
• NM_003401.5:c.746-8966C>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.746-8966C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 152,104 control chromosomes in the GnomAD database, including 797 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 0.083 (797 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• 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: 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 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.746-8966C>G		intron	N/A	NP_003392.1
	XRCC4	NM_001318012.3		c.746-8966C>G		intron	N/A	NP_001304941.1
	XRCC4	NM_022406.5		c.746-8966C>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.746-8966C>G		intron	N/A	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.746-8966C>G		intron	N/A	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.746-8966C>G		intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes AF: 0.0828 AC: 12590 AN: 151986 Hom.: 788 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0960

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0390

Gnomad OTH AF: 0.0685

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

GnomAD4 genome AF: 0.0830 AC: 12621 AN: 152104 Hom.: 797 Cov.: 32 AF XY: 0.0843 AC XY: 6265 AN XY: 74354

African (AFR) AF: 0.165 AC: 6852 AN: 41484

American (AMR) AF: 0.0531 AC: 812 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.0962 AC: 498 AN: 5178

South Asian (SAS) AF: 0.164 AC: 791 AN: 4824

European-Finnish (FIN) AF: 0.0627 AC: 664 AN: 10586

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0390 AC: 2651 AN: 67966

Other (OTH) AF: 0.0716 AC: 151 AN: 2110

Alfa AF: 0.0189 Hom.: 11

Bravo AF: 0.0852

Asia WGS AF: 0.144 AC: 501 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.75
PhyloP100		0.67
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: rs6452536; hg19: chr5-82545383;