5-83104954-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003401.5(XRCC4):c.35C>G(p.Ser12Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,613,420 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts 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 0.0072 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (18 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.58

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010462433).
• BP6: Variant 5-83104954-C-G is Benign according to our data. Variant chr5-83104954-C-G is described in ClinVar as [Benign]. Clinvar id is 787289.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00719 (1095/152194) while in subpopulation AFR AF= 0.0252 (1045/41540). AF 95% confidence interval is 0.0239. There are 16 homozygotes in gnomad4. There are 534 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC4	NM_003401.5	c.35C>G	p.Ser12Cys	missense_variant	2/8	ENST00000396027.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC4	ENST00000396027.9	c.35C>G	p.Ser12Cys	missense_variant	2/8	5	NM_003401.5	A1

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1091 AN: 152076 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00183 AC: 460 AN: 251124 Hom.: 5 AF XY: 0.00133 AC XY: 180 AN XY: 135758

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000810 AC: 1183 AN: 1461226 Hom.: 18 Cov.: 30 AF XY: 0.000677 AC XY: 492 AN XY: 726942

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152194 Hom.: 16 Cov.: 32 AF XY: 0.00718 AC XY: 534 AN XY: 74404

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.00873

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.00318 AC: 12 AN: 3474

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;.;.;T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.63
MVP		0.62
MPC		0.19
ClinPred		0.034	T
GERP RS		4.8
Varity_R		0.56
gMVP		0.40

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: rs28383138; hg19: chr5-82400773;