rs8190996

Variant names:

• chr8-30696489-G-A
• rs8190996
• NM_000637.5:c.696-10C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-30696489-G-A
• chr8-30696489-G-C

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.696-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,572,768 control chromosomes in the GnomAD database, including 160,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13723 hom., cov: 32)
  • Exomes 𝑓: 0.45 (146499 hom.)
• Consequence: GSR NM_000637.5 intron
• Scores: Splicing: ADA: 0.00001487
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.367
• Publications: 27 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-30696489-G-A is Benign according to our data. Variant chr8-30696489-G-A is described in ClinVar as Benign. ClinVar VariationId is 439766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSR	NM_000637.5	MANE Select	c.696-10C>T		intron	N/A	NP_000628.2	P00390-1
	GSR	NM_001195102.3		c.696-10C>T		intron	N/A	NP_001182031.1	P00390-3
	GSR	NM_001195103.3		c.696-10C>T		intron	N/A	NP_001182032.1	P00390-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSR	ENST00000221130.11	TSL:1 MANE Select	c.696-10C>T		intron	N/A	ENSP00000221130.5	P00390-1
	GSR	ENST00000546342.5	TSL:1	c.696-10C>T		intron	N/A	ENSP00000445516.1	P00390-3
	GSR	ENST00000541648.5	TSL:1	c.696-10C>T		intron	N/A	ENSP00000444559.1	P00390-4

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63293 AN: 151804 Hom.: 13717 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.422

GnomAD2 exomes AF: 0.452 AC: 113277 AN: 250774 AF XY: 0.454

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.452 AC: 642387 AN: 1420846 Hom.: 146499 Cov.: 26 AF XY: 0.452 AC XY: 320695 AN XY: 709648

African (AFR) AF: 0.294 AC: 9594 AN: 32590

American (AMR) AF: 0.467 AC: 20851 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9479 AN: 25886

East Asian (EAS) AF: 0.448 AC: 17688 AN: 39488

South Asian (SAS) AF: 0.457 AC: 39022 AN: 85426

European-Finnish (FIN) AF: 0.569 AC: 30365 AN: 53368

Middle Eastern (MID) AF: 0.368 AC: 2097 AN: 5698

European-Non Finnish (NFE) AF: 0.453 AC: 487049 AN: 1074616

Other (OTH) AF: 0.444 AC: 26242 AN: 59108

GnomAD4 genome AF: 0.417 AC: 63324 AN: 151922 Hom.: 13723 Cov.: 32 AF XY: 0.421 AC XY: 31279 AN XY: 74238

African (AFR) AF: 0.307 AC: 12721 AN: 41418

American (AMR) AF: 0.439 AC: 6690 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1249 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2447 AN: 5162

South Asian (SAS) AF: 0.449 AC: 2166 AN: 4824

European-Finnish (FIN) AF: 0.584 AC: 6159 AN: 10554

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.450 AC: 30560 AN: 67956

Other (OTH) AF: 0.424 AC: 893 AN: 2106

Alfa AF: 0.428 Hom.: 45785

Bravo AF: 0.402

Asia WGS AF: 0.463 AC: 1610 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hemolytic anemia due to glutathione reductase deficiency (2)
-	-	1	GSR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.67
DANN	Benign	0.56
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.080		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: rs8190996; hg19: chr8-30554006; COSMIC: COSV55319516;