rs2251780

Positions:

• chr8-30727406-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000637.5(GSR):​c.306+124C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 931,240 control chromosomes in the GnomAD database, including 16,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3230 hom., cov: 32)
  • Exomes 𝑓: 0.18 (13205 hom.)
• Consequence: GSR NM_000637.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24

Genes affected

GSR (HGNC:4623): (glutathione-disulfide reductase) This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. This enzyme is a homodimeric flavoprotein. It is a central enzyme of cellular antioxidant defense, and reduces oxidized glutathione disulfide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant. Rare mutations in this gene result in hereditary glutathione reductase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been found. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 8-30727406-G-A is Benign according to our data. Variant chr8-30727406-G-A is described in ClinVar as [Benign]. Clinvar id is 1288174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSR	NM_000637.5	c.306+124C>T		intron_variant		ENST00000221130.11	NP_000628.2
GSR	NM_001195102.3	c.306+124C>T		intron_variant			NP_001182031.1
GSR	NM_001195103.3	c.306+124C>T		intron_variant			NP_001182032.1
GSR	NM_001195104.3	c.306+124C>T		intron_variant			NP_001182033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSR	ENST00000221130.11	c.306+124C>T		intron_variant		1	NM_000637.5	ENSP00000221130	P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30327 AN: 152014 Hom.: 3220 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.176 AC: 137153 AN: 779108 Hom.: 13205 AF XY: 0.181 AC XY: 71992 AN XY: 397498

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.200 AC: 30372 AN: 152132 Hom.: 3230 Cov.: 32 AF XY: 0.202 AC XY: 15034 AN XY: 74364

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.169

Alfa AF: 0.195 Hom.: 397

Bravo AF: 0.196

Asia WGS AF: 0.216 AC: 753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.2
DANN	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs2251780; hg19: chr8-30584923;