chr5-83195855-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003401.5(XRCC4):c.401T>C(p.Ile134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,611,916 control chromosomes in the GnomAD database, including 950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.026 ( 78 hom., cov: 32)

Exomes 𝑓: 0.032 ( 872 hom. )

Consequence

XRCC4
NM_003401.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.70

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037754476).

BP6

Variant 5-83195855-T-C is Benign according to our data. Variant chr5-83195855-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1300523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0261 (3969/152142) while in subpopulation AMR AF= 0.0412 (630/15274). AF 95% confidence interval is 0.0386. There are 78 homozygotes in gnomad4. There are 1860 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5 link	c.401T>C	p.Ile134Thr	missense_variant	Exon 4 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.401T>C	p.Ile134Thr	missense_variant	Exon 4 of 8	5	NM_003401.5	ENSP00000379344.4		Q13426-2

Frequencies

GnomAD3 genomes

AF:

0.0261

AC:

3973

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00763

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0414

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0383

Gnomad OTH

AF:

0.0375

GnomAD3 exomes

AF:

0.0255

AC:

6400

AN:

250638

Hom.:

108

AF XY:

0.0266

AC XY:

3607

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00720

Gnomad AMR exome

AF:

0.0287

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0155

Gnomad FIN exome

AF:

0.00981

Gnomad NFE exome

AF:

0.0371

Gnomad OTH exome

AF:

0.0327

GnomAD4 exome

AF:

0.0320

AC:

46707

AN:

1459774

Hom.:

872

Cov.:

AF XY:

0.0320

AC XY:

23228

AN XY:

726168

show subpopulations

Gnomad4 AFR exome

AF:

0.00616

Gnomad4 AMR exome

AF:

0.0291

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0174

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.0366

Gnomad4 OTH exome

AF:

0.0309

GnomAD4 genome

AF:

0.0261

AC:

3969

AN:

152142

Hom.:

Cov.:

AF XY:

0.0250

AC XY:

1860

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00761

Gnomad4 AMR

AF:

0.0412

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.0383

Gnomad4 OTH

AF:

0.0371

Alfa

AF:

0.0336

Hom.:

159

Bravo

AF:

0.0267

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0413

AC:

159

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.0406

AC:

349

ExAC

AF:

0.0249

AC:

3029

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 30, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22466227, 16741161, 26764160) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

.;T;.;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

T;.;.;T

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.066

Sift

Benign

0.37

T;T;T;T

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.95

P;D;P;D

Vest4

0.10

MPC

0.21

ClinPred

0.017

GERP RS

5.6

Varity_R

0.16

gMVP

0.28

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