rs1805377

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_003401.5(XRCC4):c.894-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,588,702 control chromosomes in the GnomAD database, including 33,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 7046 hom., cov: 32)

Exomes 𝑓: 0.15 ( 26237 hom. )

Consequence

XRCC4
NM_003401.5 splice_region, intron

Scores

Splicing: ADA: 0.9953

Clinical Significance

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

Conservation

PhyloP100: -0.825

Publications

79 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

BP6

Variant 5-83353124-G-A is Benign according to our data. Variant chr5-83353124-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5 link	c.894-7G>A		splice_region_variant, intron_variant	Intron 7 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
XRCC4	ENST00000396027.9 link	c.894-7G>A	splice_region_variant, intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4
XRCC4	ENST00000511817.1 link	c.894-1G>A	splice_acceptor_variant, intron_variant	Intron 7 of 7	1		ENSP00000421491.1
XRCC4	ENST00000282268.7 link	c.894-7G>A	splice_region_variant, intron_variant	Intron 7 of 7	1		ENSP00000282268.3
XRCC4	ENST00000338635.10 link	c.894-1G>A	splice_acceptor_variant, intron_variant	Intron 7 of 7	2		ENSP00000342011.6

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38515

AN:

151706

Hom.:

7017

Cov.:

show subpopulations

Gnomad AFR

AF:

0.446

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.314

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.710

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.186

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.113

Gnomad OTH

AF:

0.238

GnomAD2 exomes

AF:

0.226

AC:

52222

AN:

231376

AF XY:

0.208

show subpopulations

Gnomad AFR exome

AF:

0.449

Gnomad AMR exome

AF:

0.381

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.717

Gnomad FIN exome

AF:

0.185

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.149

AC:

214456

AN:

1436878

Hom.:

26237

Cov.:

AF XY:

0.148

AC XY:

105541

AN XY:

714916

show subpopulations

African (AFR)

AF:

0.454

AC:

14286

AN:

31480

American (AMR)

AF:

0.368

AC:

14226

AN:

38710

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3621

AN:

25190

East Asian (EAS)

AF:

0.700

AC:

27303

AN:

39008

South Asian (SAS)

AF:

0.157

AC:

12870

AN:

81926

European-Finnish (FIN)

AF:

0.185

AC:

9782

AN:

52982

Middle Eastern (MID)

AF:

0.160

AC:

904

AN:

5638

European-Non Finnish (NFE)

AF:

0.109

AC:

120635

AN:

1102680

Other (OTH)

AF:

0.183

AC:

10829

AN:

59264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

7194

14388

21581

28775

35969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4878

9756

14634

19512

24390

<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:

0.254

AC:

38587

AN:

151824

Hom.:

7046

Cov.:

AF XY:

0.260

AC XY:

19250

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.447

AC:

18507

AN:

41424

American (AMR)

AF:

0.314

AC:

4773

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

524

AN:

3468

East Asian (EAS)

AF:

0.710

AC:

3680

AN:

5184

South Asian (SAS)

AF:

0.172

AC:

828

AN:

4806

European-Finnish (FIN)

AF:

0.186

AC:

1952

AN:

10502

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.113

AC:

7697

AN:

67896

Other (OTH)

AF:

0.242

AC:

512

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1262

2525

3787

5050

6312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.163

Hom.:

16008

Bravo

AF:

0.278

TwinsUK

AF:

0.109

AC:

406

ALSPAC

AF:

0.106

AC:

410

ESP6500AA

AF:

0.439

AC:

1933

ESP6500EA

AF:

0.122

AC:

1052

ExAC

AF:

0.229

AC:

27740

Asia WGS

AF:

0.410

AC:

1422

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23663450, 17557904, 19408343)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0

.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.00061

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

-0.82

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.0

GERP RS

-0.065

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.43

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.77

Position offset: 7

DS_AL_spliceai

0.99

Position offset: 1

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