8-30703370-C-T

Variant names:

• chr8-30703370-C-T
• rs3779647
• NM_000637.5:c.493-130G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000637.5(GSR):​c.493-130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 898,928 control chromosomes in the GnomAD database, including 126,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17466 hom., cov: 32)
  • Exomes 𝑓: 0.53 (108847 hom.)
• Consequence: GSR NM_000637.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.80
• Publications: 33 publications found

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]

GSR Gene-Disease associations (from GenCC):

• hemolytic anemia due to glutathione reductase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-30703370-C-T is Benign according to our data. Variant chr8-30703370-C-T is described in ClinVar as Benign. ClinVar VariationId is 1267009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000637.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSR	NM_000637.5	MANE Select	c.493-130G>A		intron	N/A	NP_000628.2
	GSR	NM_001195102.3		c.493-130G>A		intron	N/A	NP_001182031.1
	GSR	NM_001195103.3		c.493-130G>A		intron	N/A	NP_001182032.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSR	ENST00000221130.11	TSL:1 MANE Select	c.493-130G>A		intron	N/A	ENSP00000221130.5
	GSR	ENST00000546342.5	TSL:1	c.493-130G>A		intron	N/A	ENSP00000445516.1
	GSR	ENST00000541648.5	TSL:1	c.493-130G>A		intron	N/A	ENSP00000444559.1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68058 AN: 151918 Hom.: 17467 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.461

GnomAD4 exome AF: 0.532 AC: 397565 AN: 746892 Hom.: 108847 AF XY: 0.532 AC XY: 208955 AN XY: 392990

African (AFR) AF: 0.170 AC: 3302 AN: 19464

American (AMR) AF: 0.548 AC: 19192 AN: 34994

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 10810 AN: 20682

East Asian (EAS) AF: 0.395 AC: 13517 AN: 34246

South Asian (SAS) AF: 0.484 AC: 32479 AN: 67108

European-Finnish (FIN) AF: 0.635 AC: 27446 AN: 43242

Middle Eastern (MID) AF: 0.471 AC: 2037 AN: 4322

European-Non Finnish (NFE) AF: 0.556 AC: 270177 AN: 486106

Other (OTH) AF: 0.507 AC: 18605 AN: 36728

GnomAD4 genome AF: 0.448 AC: 68063 AN: 152036 Hom.: 17466 Cov.: 32 AF XY: 0.453 AC XY: 33645 AN XY: 74310

African (AFR) AF: 0.180 AC: 7470 AN: 41482

American (AMR) AF: 0.523 AC: 7977 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1764 AN: 3464

East Asian (EAS) AF: 0.425 AC: 2197 AN: 5174

South Asian (SAS) AF: 0.465 AC: 2239 AN: 4816

European-Finnish (FIN) AF: 0.646 AC: 6841 AN: 10582

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38033 AN: 67948

Other (OTH) AF: 0.462 AC: 976 AN: 2112

Alfa AF: 0.524 Hom.: 36389

Bravo AF: 0.428

Asia WGS AF: 0.430 AC: 1496 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.031
DANN	Benign	0.56
PhyloP100		-1.8
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: rs3779647; hg19: chr8-30560887;