5-83111034-A-G

Variant names:

• chr5-83111034-A-G
• rs1746416779
• NM_003401.5:c.146A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003401.5(XRCC4):​c.146A>G​(p.Glu49Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41791123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.146A>G	p.Glu49Gly	missense_variant	Exon 3 of 8	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.146A>G	p.Glu49Gly	missense_variant	Exon 3 of 8	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453382 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short stature, microcephaly, and endocrine dysfunction Uncertain:1

Mar 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;.;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T;.;.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M;M;M;M
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.093
Sift	Benign	0.11	T;T;T;T
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.65	P;P;P;P
Vest4		0.38
MutPred		0.73		Gain of glycosylation at S48 (P = 0.0413);Gain of glycosylation at S48 (P = 0.0413);Gain of glycosylation at S48 (P = 0.0413);Gain of glycosylation at S48 (P = 0.0413);
MVP		0.45
MPC		0.20
ClinPred		0.94	D
GERP RS		1.5
Varity_R		0.24
gMVP		0.43

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: rs1746416779; hg19: chr5-82406853;