5-83353158-T-G

Variant names:

• chr5-83353158-T-G
• rs1056503
• NM_003401.5:c.921T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003401.5(XRCC4):​c.921T>G​(p.Ser307Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,609,882 control chromosomes in the GnomAD database, including 34,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S307S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (7054 hom., cov: 32)
  • Exomes 𝑓: 0.15 (27552 hom.)
• Consequence: XRCC4 NM_003401.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0250
• Publications: 48 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-83353158-T-G is Benign according to our data. Variant chr5-83353158-T-G is described in ClinVar as Benign. ClinVar VariationId is 1245076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 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.921T>G	p.Ser307Ser	synonymous	Exon 8 of 8	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.927T>G	p.Ser309Ser	synonymous	Exon 8 of 8	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.927T>G	p.Ser309Ser	synonymous	Exon 8 of 8	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.921T>G	p.Ser307Ser	synonymous	Exon 8 of 8	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.927T>G	p.Ser309Ser	synonymous	Exon 8 of 8	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.921T>G	p.Ser307Ser	synonymous	Exon 8 of 8	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38568 AN: 151890 Hom.: 7025 Cov.: 32

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.233 AC: 57829 AN: 247880 AF XY: 0.214

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.723

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.152 AC: 221782 AN: 1457874 Hom.: 27552 Cov.: 31 AF XY: 0.150 AC XY: 108881 AN XY: 725260

African (AFR) AF: 0.457 AC: 15165 AN: 33162

American (AMR) AF: 0.383 AC: 16863 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3803 AN: 26020

East Asian (EAS) AF: 0.701 AC: 27649 AN: 39428

South Asian (SAS) AF: 0.159 AC: 13648 AN: 85628

European-Finnish (FIN) AF: 0.186 AC: 9902 AN: 53312

Middle Eastern (MID) AF: 0.162 AC: 931 AN: 5750

European-Non Finnish (NFE) AF: 0.110 AC: 122689 AN: 1110340

Other (OTH) AF: 0.185 AC: 11132 AN: 60188

GnomAD4 genome AF: 0.254 AC: 38640 AN: 152008 Hom.: 7054 Cov.: 32 AF XY: 0.260 AC XY: 19284 AN XY: 74310

African (AFR) AF: 0.446 AC: 18520 AN: 41486

American (AMR) AF: 0.314 AC: 4793 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3468

East Asian (EAS) AF: 0.710 AC: 3668 AN: 5168

South Asian (SAS) AF: 0.172 AC: 829 AN: 4816

European-Finnish (FIN) AF: 0.186 AC: 1969 AN: 10578

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7712 AN: 67926

Other (OTH) AF: 0.242 AC: 511 AN: 2114

Alfa AF: 0.159 Hom.: 2688

Bravo AF: 0.279

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Short stature, microcephaly, and endocrine dysfunction (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.59
PhyloP100		-0.025
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: rs1056503; hg19: chr5-82648977; COSMIC: COSV56535247;