5-83204915-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003401.5(XRCC4):c.739G>T(p.Ala247Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,608,646 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 35 hom., cov: 32)

Exomes 𝑓: 0.015 ( 366 hom. )

Consequence

XRCC4
NM_003401.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.216

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

short stature, microcephaly, and endocrine dysfunction
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
microcephalic primordial dwarfism-insulin resistance syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

XRCC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029673278).

BP6

Variant 5-83204915-G-T is Benign according to our data. Variant chr5-83204915-G-T is described in ClinVar as Benign. ClinVar VariationId is 1260275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5 link	c.739G>T	p.Ala247Ser	missense_variant	Exon 6 of 8	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9 link	c.739G>T	p.Ala247Ser	missense_variant	Exon 6 of 8	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2347

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00847

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0691

Gnomad SAS

AF:

0.0310

Gnomad FIN

AF:

0.0449

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0229

AC:

5743

AN:

250266

AF XY:

0.0227

show subpopulations

Gnomad AFR exome

AF:

0.00753

Gnomad AMR exome

AF:

0.0361

Gnomad ASJ exome

AF:

0.000996

Gnomad EAS exome

AF:

0.0596

Gnomad FIN exome

AF:

0.0408

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0148

AC:

21560

AN:

1456538

Hom.:

366

Cov.:

AF XY:

0.0153

AC XY:

11075

AN XY:

724778

show subpopulations

African (AFR)

AF:

0.00767

AC:

256

AN:

33376

American (AMR)

AF:

0.0322

AC:

1438

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.000770

AC:

AN:

25966

East Asian (EAS)

AF:

0.0771

AC:

3049

AN:

39544

South Asian (SAS)

AF:

0.0323

AC:

2769

AN:

85802

European-Finnish (FIN)

AF:

0.0399

AC:

2121

AN:

53142

Middle Eastern (MID)

AF:

0.00662

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00989

AC:

10964

AN:

1108214

Other (OTH)

AF:

0.0151

AC:

905

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

875

1750

2624

3499

4374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

488

976

1464

1952

2440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2346

AN:

152108

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1282

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00850

AC:

353

AN:

41542

American (AMR)

AF:

0.0177

AC:

271

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.0695

AC:

359

AN:

5168

South Asian (SAS)

AF:

0.0306

AC:

147

AN:

4810

European-Finnish (FIN)

AF:

0.0449

AC:

476

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

704

AN:

67950

Other (OTH)

AF:

0.0114

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

120

241

361

482

602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.0132

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.0226

AC:

2745

Asia WGS

AF:

0.0490

AC:

170

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25360583, 23788213, 24378850, 18630527, 18246529)

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

0.076

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.75

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0

.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.42

T;.;.;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

M;M;M;M

PhyloP100

0.22

PrimateAI

Benign

0.25

PROVEAN

Benign

0.19

N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.32

T;T;T;T

Sift4G

Benign

0.61

T;T;T;T

Vest4

0.033

ClinPred

0.0046

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.078

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over