rs7734849

Variant names:

• chr5-83344130-T-A
• rs7734849
• NM_003401.5:c.894-9001T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-83344130-T-A
• chr5-83344130-T-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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.

• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.894-9001T>A		intron	N/A	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.894-8995T>A		intron	N/A	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.894-8995T>A		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.894-9001T>A		intron	N/A	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.894-8995T>A		intron	N/A	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.894-9001T>A		intron	N/A	ENSP00000282268.3	Q13426-2

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

African (AFR) AF: 0.438 AC: 17571 AN: 40160

American (AMR) AF: 0.312 AC: 4631 AN: 14860

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 433 AN: 3354

East Asian (EAS) AF: 0.704 AC: 3608 AN: 5128

South Asian (SAS) AF: 0.171 AC: 792 AN: 4638

European-Finnish (FIN) AF: 0.184 AC: 1834 AN: 9982

Middle Eastern (MID) AF: 0.164 AC: 46 AN: 280

European-Non Finnish (NFE) AF: 0.114 AC: 7620 AN: 66854

Other (OTH) AF: 0.239 AC: 492 AN: 2056

Alfa AF: 0.197 Hom.: 395

Bravo AF: 0.271

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.35
PhyloP100		-1.3
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: rs7734849; hg19: chr5-82639949; COSMIC: COSV56535118;