dbSNP rs28360317: XRCC4:c.894-29390_894-29389insCCT (chr5-83323739-A-ACTC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003401.5(XRCC4):c.894-29390_894-29389insCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 151,744 control chromosomes in the GnomAD database, including 7,490 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 7490 hom., cov: 27)

Consequence

XRCC4
NM_003401.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.132

Publications

17 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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
XRCC4	NM_003401.5	MANE Select	c.894-29390_894-29389insCCT	intron	N/A	NP_003392.1
XRCC4	NM_001318012.3		c.894-29384_894-29383insCCT	intron	N/A	NP_001304941.1
XRCC4	NM_022406.5		c.894-29384_894-29383insCCT	intron	N/A	NP_071801.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.894-29392_894-29391insCTC	intron	N/A	ENSP00000379344.4
XRCC4	ENST00000511817.1	TSL:1	c.894-29386_894-29385insCTC	intron	N/A	ENSP00000421491.1
XRCC4	ENST00000282268.7	TSL:1	c.894-29392_894-29391insCTC	intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

36953

AN:

151626

Hom.:

7451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.493

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.708

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.0795

Gnomad OTH

AF:

0.219

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.244

AC:

37043

AN:

151744

Hom.:

7490

Cov.:

AF XY:

0.247

AC XY:

18336

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.494

AC:

20373

AN:

41266

American (AMR)

AF:

0.288

AC:

4387

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

537

AN:

3468

East Asian (EAS)

AF:

0.708

AC:

3634

AN:

5134

South Asian (SAS)

AF:

0.159

AC:

768

AN:

4826

European-Finnish (FIN)

AF:

0.130

AC:

1376

AN:

10572

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0795

AC:

5403

AN:

67944

Other (OTH)

AF:

0.226

AC:

476

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1098

2197

3295

4394

5492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.178

Hom.:

489

Bravo

AF:

0.273

Asia WGS

AF:

0.414

AC:

1433

AN:

3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over