rs1805377

Positions:

• chr5-83353124-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The ENST00000511817.1(XRCC4):​c.894-1G>A variant causes a splice acceptor 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 ENST00000511817.1 splice_acceptor
• 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 -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.65479726 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/exons	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000511817.1	c.894-1G>A		splice_acceptor_variant		1		ENSP00000421491	P3
XRCC4	ENST00000396027.9	c.894-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_003401.5	ENSP00000379344	A1
XRCC4	ENST00000282268.7	c.894-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000282268	A1
XRCC4	ENST00000338635.10	c.894-1G>A		splice_acceptor_variant		2		ENSP00000342011	P3

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2018	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
MutationTaster	Benign	1.0	P;P;P;P
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;