NM_003401.5:c.25delC

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 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:12
• Conservation: PhyloP100: 0.869

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-83104942-TC-T is Pathogenic according to our data. Variant chr5-83104942-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83104942-TC-T is described in Lovd as [Pathogenic]. Variant chr5-83104942-TC-T is described in Lovd as [Likely_pathogenic]. Variant chr5-83104942-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.25delC	p.His9ThrfsTer8	frameshift_variant	Exon 2 of 8	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.25delC	p.His9ThrfsTer8	frameshift_variant	Exon 2 of 8	5	NM_003401.5	ENSP00000379344.4

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

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251062 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135710

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 SAS exome AF: 0.000262

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000497

Gnomad4 OTH exome AF: 0.000331

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

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.00

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate impaired non-homologous end joining (PMID: 25728776); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26822949, 25839420, 31980526, 34426522, 25728776, 35595529) -

Sep 28, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.His9Thrfs*8) in the XRCC4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XRCC4 are known to be pathogenic (PMID: 25728776). This variant is present in population databases (rs757928483, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with short stature, microcephaly, and endocrine dysfunction (PMID: 25728776, 25839420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208515). For these reasons, this variant has been classified as Pathogenic. -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

XRCC4: PVS1, PM2 -

Short stature, microcephaly, and endocrine dysfunction Pathogenic:6

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide deletion (delC) in exon 2 of 8 of the XRCC4 gene and results in an early termination codon 8 amino acids downstream of the frameshift introduced at codon 9. This variant is predicted to generate a non-functional allele through either the expression of a truncated protein or a loss of X-ray repair cross complementing 4 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 208515) that has been observed in compound heterozygous individuals affected by microcephaly, primordial dwarfism and/or short stature (PMID: 25728776, 25839420, 27169690). This variant is present in 673 of 1,613,268 alleles (0.04%) in the gnomAD population dataset. Immunoblots of proteins derived from the cultured fibroblast cells of a compound heterozygous individual confirmed that this variant results in a significantly reduced production of the XRCC4 protein (PMID: 25728776). Haploinsufficiency in XRCC4 is a known mechanism of disease (PMID: 25728776). Based upon the evidence, we consider this a likely pathogenic variant. ACMG Criteria: PM3, PVS1 -

Jul 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 27, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.His9ThrfsX8 variant in XRCC4 has been reported in the compound heterozygous state in 4 individuals with clinical features of primordial microcephalic dwarfism and segregated with disease in 1 affected relative (Murray 2015 PMID: 25728776, Rosin 2015 PMID: 25839420). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 208515) and been identified in 0.083% (107/128924) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 9 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the XRCC4 gene has been strongly associated with short stature, microcephaly, and endocrine dysfunction. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive short stature, microcephaly, and endocrine dysfunction. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1. -

-

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

XRCC4 c.25delC, [p.H9fs] is a frameshift variant predicted to result in premature truncation or absence of XRCC4 protein. This variant has previously been reported in microcephaly and prenatal-onset global growth failure and is considered likely pathogenic (PMID:25728776; 25839420). -

Nov 22, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: XRCC4 c.25delC (p.His9ThrfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00039 in 251062 control chromosomes. c.25delC has been reported in the literature in individuals affected with Microcephaly, primordial dwarfism, and unilateral renal agenesis (Murray_2015, Rosin_2015), and these individuals were reported as compound heterozygous, carrying other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320677; hg19: chr5-82400761;