chr5-83105046-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

XRCC4
NM_003401.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

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 link	c.127T>C	p.Trp43Arg	missense_variant	Exon 2 of 8	ENST00000396027.9	NP_003392.1	Q13426-2A0A024RAL0Q7Z763

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9 link	c.127T>C	p.Trp43Arg	missense_variant	Exon 2 of 8	5	NM_003401.5	ENSP00000379344.4		Q13426-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250224

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135256

show subpopulations

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 SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460594

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726576

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00152

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2016	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. -

Short stature, microcephaly, and endocrine dysfunction

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 23, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -

Ateleiotic dwarfism

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

- -

XRCC4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2024

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

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T;.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

T;.;.;T

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.8

M;M;M;M

PrimateAI

Uncertain

0.64

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

GERP RS

5.7

Varity_R

0.98

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over