NM_003401.5:c.894-7G>A

Variant names:

• chr5-83353124-G-A
• rs1805377
• NM_003401.5:c.894-7G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_003401.5(XRCC4):​c.894-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,588,702 control chromosomes in the GnomAD database, including 33,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (7046 hom., cov: 32)
  • Exomes 𝑓: 0.15 (26237 hom.)
• Consequence: XRCC4 NM_003401.5 splice_region, intron
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.825

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• BP6: Variant 5-83353124-G-A is Benign according to our data. Variant chr5-83353124-G-A is described in ClinVar as [Benign]. Clinvar id is 1237727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-7G>A		splice_region_variant, intron_variant	Intron 7 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.894-7G>A		splice_region_variant, intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4
XRCC4	ENST00000511817.1	c.894-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 7	1		ENSP00000421491.1
XRCC4	ENST00000282268.7	c.894-7G>A		splice_region_variant, intron_variant	Intron 7 of 7	1		ENSP00000282268.3
XRCC4	ENST00000338635.10	c.894-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 7	2		ENSP00000342011.6

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38515 AN: 151706 Hom.: 7017 Cov.: 32

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.238

GnomAD3 exomes AF: 0.226 AC: 52222 AN: 231376 Hom.: 9749 AF XY: 0.208 AC XY: 26176 AN XY: 125682

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.381

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.717

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.149 AC: 214456 AN: 1436878 Hom.: 26237 Cov.: 29 AF XY: 0.148 AC XY: 105541 AN XY: 714916

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.254 AC: 38587 AN: 151824 Hom.: 7046 Cov.: 32 AF XY: 0.260 AC XY: 19250 AN XY: 74174

Gnomad4 AFR AF: 0.447

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: 0.113

Gnomad4 OTH AF: 0.242

Alfa AF: 0.150 Hom.: 7056

Bravo AF: 0.278

TwinsUK AF: 0.109 AC: 406

ALSPAC AF: 0.106 AC: 410

ESP6500AA AF: 0.439 AC: 1933

ESP6500EA AF: 0.122 AC: 1052

ExAC AF: 0.229 AC: 27740

Asia WGS AF: 0.410 AC: 1422 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23663450, 17557904, 19408343) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.46
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.00061	N
GERP RS		-0.065

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.43
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.77		Position offset: 7
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1805377; hg19: chr5-82648943; COSMIC: COSV56535232;