rs1478485

Variant names:

• chr5-83084708-G-A
• rs1478485
• NM_003401.5:c.-11+7093G>A

Variant summary

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

The NM_003401.5(XRCC4):​c.-11+7093G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 151,884 control chromosomes in the GnomAD database, including 19,008 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 0.49 (19008 hom., cov: 31)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.303
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.-11+7093G>A		intron_variant	Intron 1 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.-11+7093G>A		intron_variant	Intron 1 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74320 AN: 151766 Hom.: 18987 Cov.: 31

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.456

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

GnomAD4 genome AF: 0.490 AC: 74374 AN: 151884 Hom.: 19008 Cov.: 31 AF XY: 0.487 AC XY: 36155 AN XY: 74212

African (AFR) AF: 0.627 AC: 25978 AN: 41420

American (AMR) AF: 0.347 AC: 5290 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1350 AN: 3464

East Asian (EAS) AF: 0.194 AC: 1003 AN: 5168

South Asian (SAS) AF: 0.515 AC: 2474 AN: 4808

European-Finnish (FIN) AF: 0.494 AC: 5215 AN: 10546

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.464 AC: 31509 AN: 67908

Other (OTH) AF: 0.455 AC: 958 AN: 2106

Alfa AF: 0.481 Hom.: 2217

Bravo AF: 0.478

Asia WGS AF: 0.371 AC: 1290 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.81
PhyloP100		0.30
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: rs1478485; hg19: chr5-82380527;