rs869320677

Variant names:

• chr5-83104942-TC-T
• rs869320677
• NM_003401.5:c.25delC

Your query was ambiguous. Multiple possible variants found:

• chr5-83104942-TC-T
• chr5-83104942-TC-TCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_003401.5(XRCC4):​c.25delC​(p.His9ThrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,613,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: XRCC4 NM_003401.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 0.869
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PP5: Variant 5-83104942-TC-T is Pathogenic according to our data. Variant chr5-83104942-TC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.25delC	p.His9ThrfsTer8	frameshift	Exon 2 of 8	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.25delC	p.His9ThrfsTer8	frameshift	Exon 2 of 8	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.25delC	p.His9ThrfsTer8	frameshift	Exon 2 of 8	NP_071801.1	Q13426-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.25delC	p.His9ThrfsTer8	frameshift	Exon 2 of 8	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.25delC	p.His9ThrfsTer8	frameshift	Exon 2 of 8	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.25delC	p.His9ThrfsTer8	frameshift	Exon 2 of 8	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000394 AC: 99 AN: 251062 AF XY: 0.000405

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000696

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000420 AC: 613 AN: 1461012 Hom.: 0 Cov.: 30 AF XY: 0.000407 AC XY: 296 AN XY: 726850

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000448 AC: 2 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86220

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.000497 AC: 552 AN: 1111474

Other (OTH) AF: 0.000331 AC: 20 AN: 60344

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74446

African (AFR) AF: 0.0000722 AC: 3 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000264

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Short stature, microcephaly, and endocrine dysfunction (8)
6	-	-	not provided (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87
Mutation Taster		=14/186	disease causing (ClinVar)

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: rs869320677; hg19: chr5-82400761;