chr5-83105046-T-C

Variant names:

• chr5-83105046-T-C
• rs587779351
• NM_003401.5:c.127T>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003401.5(XRCC4):​c.127T>C​(p.Trp43Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.19

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

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS1: Transcript NM_003401.5 (XRCC4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1329084
• PM1: In a strand (size 6) in uniprot entity XRCC4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003401.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 5-83105046-T-C is Pathogenic according to our data. Variant chr5-83105046-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83105046-T-C is described in Lovd as [Pathogenic]. Variant chr5-83105046-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.127T>C	p.Trp43Arg	missense_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.127T>C	p.Trp43Arg	missense_variant	Exon 2 of 8	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250224 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460594 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726576

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33374

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44572

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26082

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39574

Gnomad4 SAS exome AF: 0.000128 AC: 11 AN: 86048

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53400

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111466

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000259 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 13, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W43R pathogenic variant in the XRCC4 gene has been reported previously in the homozygous state in at least two individuals with microcephalic primordial dwarfism (Shaheen et al., 2014; Murray et al., 2015). Functional studies demonstrate that this variant impairs XRCC4 function and results in greatly reduced protein levels as compared to wild type (Murray et al., 2015; Guo et al., 2015). The W43R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W43R as a pathogenic variant. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Short stature, microcephaly, and endocrine dysfunction Pathogenic:2

Jul 23, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ateleiotic dwarfism Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

XRCC4-related disorder Pathogenic:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The XRCC4 c.127T>C variant is predicted to result in the amino acid substitution p.Trp43Arg. This variant has been reported in the homozygous state in individuals with short stature and microcephaly (Shaheen et al. 2014. PubMed ID: 24389050; Shaheen et al. 2018. PubMed ID: 30214071; Asa et al. 2021. PubMed ID: 33842963). Functional studies showed that this variant impacts protein functions (Murray et al. 2015. PubMed ID: 25728776; Asa et al. 2021. PubMed ID: 33842963). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;.;.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.99
MutPred		0.89		Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);
MVP		0.86
MPC		0.24
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.79
Mutation Taster		=2/98	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

Publications

LitVar

Other links and lift over

dbSNP: rs587779351; hg19: chr5-82400865;