8-30689119-T-C

Variant names:

• chr8-30689119-T-C
• rs2551715
• NM_000637.5:c.1041+42A>G

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.1041+42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,588,110 control chromosomes in the GnomAD database, including 289,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29903 hom., cov: 31)
  • Exomes 𝑓: 0.60 (259177 hom.)
• Consequence: GSR NM_000637.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.12
• Publications: 20 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=-0.83).
• BP6: Variant 8-30689119-T-C is Benign according to our data. Variant chr8-30689119-T-C is described in ClinVar as Benign. ClinVar VariationId is 1252531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 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.1041+42A>G		intron	N/A	NP_000628.2	P00390-1
	GSR	NM_001195102.3		c.954+42A>G		intron	N/A	NP_001182031.1	P00390-3
	GSR	NM_001195103.3		c.882+3850A>G		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.1041+42A>G		intron	N/A	ENSP00000221130.5	P00390-1
	GSR	ENST00000546342.5	TSL:1	c.954+42A>G		intron	N/A	ENSP00000445516.1	P00390-3
	GSR	ENST00000541648.5	TSL:1	c.882+3850A>G		intron	N/A	ENSP00000444559.1	P00390-4

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94738 AN: 151794 Hom.: 29882 Cov.: 31

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.644

GnomAD2 exomes AF: 0.594 AC: 147750 AN: 248744 AF XY: 0.595

Gnomad AFR exome AF: 0.719

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.763

Gnomad EAS exome AF: 0.547

Gnomad FIN exome AF: 0.544

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.599 AC: 859670 AN: 1436198 Hom.: 259177 Cov.: 26 AF XY: 0.598 AC XY: 428160 AN XY: 715778

African (AFR) AF: 0.711 AC: 23429 AN: 32942

American (AMR) AF: 0.526 AC: 23337 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19855 AN: 25958

East Asian (EAS) AF: 0.531 AC: 20994 AN: 39550

South Asian (SAS) AF: 0.578 AC: 49480 AN: 85630

European-Finnish (FIN) AF: 0.545 AC: 29075 AN: 53314

Middle Eastern (MID) AF: 0.681 AC: 3889 AN: 5710

European-Non Finnish (NFE) AF: 0.599 AC: 652772 AN: 1089176

Other (OTH) AF: 0.618 AC: 36839 AN: 59562

GnomAD4 genome AF: 0.624 AC: 94805 AN: 151912 Hom.: 29903 Cov.: 31 AF XY: 0.620 AC XY: 46017 AN XY: 74236

African (AFR) AF: 0.713 AC: 29574 AN: 41462

American (AMR) AF: 0.556 AC: 8465 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2632 AN: 3468

East Asian (EAS) AF: 0.559 AC: 2877 AN: 5146

South Asian (SAS) AF: 0.573 AC: 2757 AN: 4810

European-Finnish (FIN) AF: 0.545 AC: 5747 AN: 10540

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40687 AN: 67942

Other (OTH) AF: 0.642 AC: 1357 AN: 2114

Alfa AF: 0.613 Hom.: 110945

Bravo AF: 0.631

Asia WGS AF: 0.579 AC: 2014 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.30
DANN	Benign	0.54
PhyloP100		-1.1
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: rs2551715; hg19: chr8-30546636; COSMIC: COSV55320857;