Genetic Variant XRCC4:p.Ser307Ser (chr5-83353158-T-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 -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 id 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

GnomAD3 exomes

AF:

0.233

AC:

57829

AN:

247880

Hom.:

11025

AF XY:

0.214

AC XY:

28746

AN XY:

134114

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 SAS exome

AF:

0.156

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

Gnomad4 AFR exome

AF:

0.457

Gnomad4 AMR exome

AF:

0.383

Gnomad4 ASJ exome

AF:

0.146

Gnomad4 EAS exome

AF:

0.701

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.186

Gnomad4 NFE exome

AF:

0.110

Gnomad4 OTH exome

AF:

0.185

GnomAD4 genome

AF:

0.254

AC:

38640

AN:

152008

Hom.:

7054

Cov.:

AF XY:

0.260

AC XY:

19284

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.446

Gnomad4 AMR

AF:

0.314

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.710

Gnomad4 SAS

AF:

0.172

Gnomad4 FIN

AF:

0.186

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.242

Alfa

AF:

0.154

Hom.:

1968

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

DANN

Benign

0.59

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