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
• Publications: 80 publications found

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]

XRCC4 Gene-Disease associations (from GenCC):

• short stature, microcephaly, and endocrine dysfunction

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022406.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.894-7G>A		splice_region intron	N/A	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.894-1G>A		splice_acceptor intron	N/A	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.894-1G>A		splice_acceptor intron	N/A	NP_071801.1	Q13426-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.894-7G>A		splice_region intron	N/A	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.894-1G>A		splice_acceptor intron	N/A	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.894-7G>A		splice_region intron	N/A	ENSP00000282268.3	Q13426-2

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

African (AFR) AF: 0.454 AC: 14286 AN: 31480

American (AMR) AF: 0.368 AC: 14226 AN: 38710

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3621 AN: 25190

East Asian (EAS) AF: 0.700 AC: 27303 AN: 39008

South Asian (SAS) AF: 0.157 AC: 12870 AN: 81926

European-Finnish (FIN) AF: 0.185 AC: 9782 AN: 52982

Middle Eastern (MID) AF: 0.160 AC: 904 AN: 5638

European-Non Finnish (NFE) AF: 0.109 AC: 120635 AN: 1102680

Other (OTH) 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

African (AFR) AF: 0.447 AC: 18507 AN: 41424

American (AMR) AF: 0.314 AC: 4773 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3468

East Asian (EAS) AF: 0.710 AC: 3680 AN: 5184

South Asian (SAS) AF: 0.172 AC: 828 AN: 4806

European-Finnish (FIN) AF: 0.186 AC: 1952 AN: 10502

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7697 AN: 67896

Other (OTH) AF: 0.242 AC: 512 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.82
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

Other links and lift over

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