chr5-83353158-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003401.5(XRCC4):c.921T>G(p.Ser307Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,609,882 control chromosomes in the GnomAD database, including 34,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S307S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.25 ( 7054 hom., cov: 32)

Exomes 𝑓: 0.15 ( 27552 hom. )

Consequence

XRCC4
NM_003401.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0250

Publications

48 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 5-83353158-T-G is Benign according to our data. Variant chr5-83353158-T-G is described in ClinVar as Benign. ClinVar VariationId is 1245076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.025 with no splicing effect.

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.921T>G	p.Ser307Ser	synonymous_variant	Exon 8 of 8	ENST00000396027.9	NP_003392.1	Q13426-2A0A024RAL0Q7Z763

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
XRCC4	ENST00000396027.9 link	c.921T>G	p.Ser307Ser	synonymous_variant	Exon 8 of 8	5	NM_003401.5	ENSP00000379344.4	Q13426-2
XRCC4	ENST00000511817.1 link	c.927T>G	p.Ser309Ser	synonymous_variant	Exon 8 of 8	1		ENSP00000421491.1	Q13426-1
XRCC4	ENST00000282268.7 link	c.921T>G	p.Ser307Ser	synonymous_variant	Exon 8 of 8	1		ENSP00000282268.3	Q13426-2
XRCC4	ENST00000338635.10 link	c.927T>G	p.Ser309Ser	synonymous_variant	Exon 8 of 8	2		ENSP00000342011.6	Q13426-1

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38568

AN:

151890

Hom.:

7025

Cov.:

show subpopulations

Gnomad AFR

AF:

0.446

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.314

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.710

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.186

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.233

AC:

57829

AN:

247880

AF XY:

0.214

show subpopulations

Gnomad AFR exome

AF:

0.450

Gnomad AMR exome

AF:

0.397

Gnomad ASJ exome

AF:

0.144

Gnomad EAS exome

AF:

0.723

Gnomad FIN exome

AF:

0.187

Gnomad NFE exome

AF:

0.114

Gnomad OTH exome

AF:

0.187

GnomAD4 exome

AF:

0.152

AC:

221782

AN:

1457874

Hom.:

27552

Cov.:

AF XY:

0.150

AC XY:

108881

AN XY:

725260

show subpopulations

African (AFR)

AF:

0.457

AC:

15165

AN:

33162

American (AMR)

AF:

0.383

AC:

16863

AN:

44046

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

3803

AN:

26020

East Asian (EAS)

AF:

0.701

AC:

27649

AN:

39428

South Asian (SAS)

AF:

0.159

AC:

13648

AN:

85628

European-Finnish (FIN)

AF:

0.186

AC:

9902

AN:

53312

Middle Eastern (MID)

AF:

0.162

AC:

931

AN:

5750

European-Non Finnish (NFE)

AF:

0.110

AC:

122689

AN:

1110340

Other (OTH)

AF:

0.185

AC:

11132

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

7844

15689

23533

31378

39222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4972

9944

14916

19888

24860

<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:

38640

AN:

152008

Hom.:

7054

Cov.:

AF XY:

0.260

AC XY:

19284

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.446

AC:

18520

AN:

41486

American (AMR)

AF:

0.314

AC:

4793

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

524

AN:

3468

East Asian (EAS)

AF:

0.710

AC:

3668

AN:

5168

South Asian (SAS)

AF:

0.172

AC:

829

AN:

4816

European-Finnish (FIN)

AF:

0.186

AC:

1969

AN:

10578

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7712

AN:

67926

Other (OTH)

AF:

0.242

AC:

511

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1251

2503

3754

5006

6257

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:

0.159

Hom.:

2688

Bravo

AF:

0.279

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Short stature, microcephaly, and endocrine dysfunction

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.3

(source)

DANN

Benign

0.59

PhyloP100

-0.025

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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