rs1805377

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_022406.5(XRCC4):​c.894-1G>A variant causes a splice acceptor, 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_022406.5 splice_acceptor, 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

Our verdict: Benign. The variant received -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.6290801 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 6, new splice context is: gattttcttttcaattctAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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

GnomAD2 exomes AF: 0.226 AC: 52222 AN: 231376 AF XY: 0.208

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 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 AC: 14286 AN: 31480

Gnomad4 AMR exome AF: 0.368 AC: 14226 AN: 38710

Gnomad4 ASJ exome AF: 0.144 AC: 3621 AN: 25190

Gnomad4 EAS exome AF: 0.700 AC: 27303 AN: 39008

Gnomad4 SAS exome AF: 0.157 AC: 12870 AN: 81926

Gnomad4 FIN exome AF: 0.185 AC: 9782 AN: 52982

Gnomad4 NFE exome AF: 0.109 AC: 120635 AN: 1102680

Gnomad4 Remaining exome AF: 0.183 AC: 10829 AN: 59264

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 AC: 0.44677 AN: 0.44677

Gnomad4 AMR AF: 0.314 AC: 0.313518 AN: 0.313518

Gnomad4 ASJ AF: 0.151 AC: 0.151096 AN: 0.151096

Gnomad4 EAS AF: 0.710 AC: 0.709877 AN: 0.709877

Gnomad4 SAS AF: 0.172 AC: 0.172285 AN: 0.172285

Gnomad4 FIN AF: 0.186 AC: 0.185869 AN: 0.185869

Gnomad4 NFE AF: 0.113 AC: 0.113365 AN: 0.113365

Gnomad4 OTH AF: 0.242 AC: 0.242195 AN: 0.242195

Alfa AF: 0.163 Hom.: 16008

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
Mutation Taster		=99/1	polymorphism (auto)

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;