chr5-83100055-C-T

Variant names:

• chr5-83100055-C-T
• rs13180356
• NM_003401.5:c.-10-4855C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003401.5(XRCC4):​c.-10-4855C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,056 control chromosomes in the GnomAD database, including 2,981 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 0.18 (2981 hom., cov: 32)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.-10-4855C>T		intron	N/A	NP_003392.1
	XRCC4	NM_001318012.3		c.-10-4855C>T		intron	N/A	NP_001304941.1
	XRCC4	NM_022406.5		c.-10-4855C>T		intron	N/A	NP_071801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.-10-4855C>T		intron	N/A	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.-10-4855C>T		intron	N/A	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.-10-4855C>T		intron	N/A	ENSP00000282268.3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27086 AN: 151936 Hom.: 2980 Cov.: 32

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.178 AC: 27093 AN: 152056 Hom.: 2981 Cov.: 32 AF XY: 0.174 AC XY: 12963 AN XY: 74306

African (AFR) AF: 0.0517 AC: 2147 AN: 41526

American (AMR) AF: 0.192 AC: 2928 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 771 AN: 3464

East Asian (EAS) AF: 0.0555 AC: 287 AN: 5170

South Asian (SAS) AF: 0.182 AC: 877 AN: 4826

European-Finnish (FIN) AF: 0.206 AC: 2177 AN: 10560

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17223 AN: 67950

Other (OTH) AF: 0.173 AC: 365 AN: 2110

Alfa AF: 0.225 Hom.: 11862

Bravo AF: 0.170

Asia WGS AF: 0.128 AC: 447 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.45
DANN	Benign	0.57
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13180356; hg19: chr5-82395874;