chr5-83300362-A-T

Variant names:

• chr5-83300362-A-T
• rs301279
• NM_003401.5:c.893+41685A>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.893+41685A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 152,036 control chromosomes in the GnomAD database, including 54,901 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 0.85 (54901 hom., cov: 30)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 5 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.893+41685A>T		intron_variant	Intron 7 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.893+41685A>T		intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.849 AC: 128973 AN: 151918 Hom.: 54863 Cov.: 30

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.907

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.921

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.871

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

GnomAD4 genome AF: 0.849 AC: 129062 AN: 152036 Hom.: 54901 Cov.: 30 AF XY: 0.846 AC XY: 62819 AN XY: 74290

African (AFR) AF: 0.825 AC: 34216 AN: 41466

American (AMR) AF: 0.875 AC: 13357 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.921 AC: 3198 AN: 3472

East Asian (EAS) AF: 0.863 AC: 4460 AN: 5166

South Asian (SAS) AF: 0.785 AC: 3780 AN: 4818

European-Finnish (FIN) AF: 0.774 AC: 8159 AN: 10538

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.868 AC: 58982 AN: 67988

Other (OTH) AF: 0.869 AC: 1837 AN: 2114

Alfa AF: 0.851 Hom.: 6861

Bravo AF: 0.854

Asia WGS AF: 0.808 AC: 2810 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	7.1
DANN	Benign	0.81
PhyloP100		-0.018
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: rs301279; hg19: chr5-82596181;