chr5-83344130-T-A

Position:

• chr5-83344130-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003401.5(XRCC4):​c.894-9001T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 148,208 control chromosomes in the GnomAD database, including 6,565 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (6565 hom., cov: 27)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-9001T>A		intron_variant		ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.894-9001T>A		intron_variant		5	NM_003401.5	ENSP00000379344	A1
XRCC4	ENST00000282268.7	c.894-9001T>A		intron_variant		1		ENSP00000282268	A1
XRCC4	ENST00000511817.1	c.894-8995T>A		intron_variant		1		ENSP00000421491	P3
XRCC4	ENST00000338635.10	c.894-8995T>A		intron_variant		2		ENSP00000342011	P3

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37022 AN: 148092 Hom.: 6543 Cov.: 27

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.235

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.250 AC: 37081 AN: 148208 Hom.: 6565 Cov.: 27 AF XY: 0.256 AC XY: 18479 AN XY: 72316

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.239

Alfa AF: 0.197 Hom.: 395

Bravo AF: 0.271

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.35

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: rs7734849; hg19: chr5-82639949; COSMIC: COSV56535118;