rs3734091

chr5-83204915-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (35 hom., cov: 32)
  • Exomes 𝑓: 0.015 (366 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.216

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
XRCC4	NM_003401.5	c.739G>T	p.Ala247Ser	missense_variant	6/8	ENST00000396027.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC4	ENST00000396027.9	c.739G>T	p.Ala247Ser	missense_variant	6/8	5	NM_003401.5	A1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2347 AN: 151990 Hom.: 35 Cov.: 32

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

GnomAD3 exomes AF: 0.0229 AC: 5743 AN: 250266 Hom.: 113 AF XY: 0.0227 AC XY: 3075 AN XY: 135326

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 SAS exome AF: 0.0338

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.: 29 AF XY: 0.0153 AC XY: 11075 AN XY: 724778

Gnomad4 AFR exome AF: 0.00767

Gnomad4 AMR exome AF: 0.0322

Gnomad4 ASJ exome AF: 0.000770

Gnomad4 EAS exome AF: 0.0771

Gnomad4 SAS exome AF: 0.0323

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.00989

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0154 AC: 2346 AN: 152108 Hom.: 35 Cov.: 32 AF XY: 0.0172 AC XY: 1282 AN XY: 74368

Gnomad4 AFR AF: 0.00850

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0695

Gnomad4 SAS AF: 0.0306

Gnomad4 FIN AF: 0.0449

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0113 Hom.: 36

Bravo AF: 0.0132

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0113 AC: 97

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 25360583, 23788213, 24378850, 18630527, 18246529) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.75
Dann	Benign	0.74
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.42	T;.;.;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
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
Polyphen		0.023	B;B;B;B
Vest4		0.033
MPC		0.19
ClinPred		0.0046	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.078

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

Other links and lift over

dbSNP: rs3734091; hg19: chr5-82500734; COSMIC: COSV56547164; COSMIC: COSV56547164;