8-30727406-G-A

Variant names:

• chr8-30727406-G-A
• rs2251780
• NM_000637.5:c.306+124C>T

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.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
• Publications: 10 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=-0.75).
• BP6: Variant 8-30727406-G-A is Benign according to our data. Variant chr8-30727406-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

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.306+124C>T		intron	N/A	NP_000628.2	P00390-1
	GSR	NM_001195102.3		c.306+124C>T		intron	N/A	NP_001182031.1	P00390-3
	GSR	NM_001195103.3		c.306+124C>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.306+124C>T		intron	N/A	ENSP00000221130.5	P00390-1
	GSR	ENST00000546342.5	TSL:1	c.306+124C>T		intron	N/A	ENSP00000445516.1	P00390-3
	GSR	ENST00000541648.5	TSL:1	c.306+124C>T		intron	N/A	ENSP00000444559.1	P00390-4

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

African (AFR) AF: 0.255 AC: 4213 AN: 16494

American (AMR) AF: 0.181 AC: 4874 AN: 26954

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 3101 AN: 19290

East Asian (EAS) AF: 0.162 AC: 4349 AN: 26900

South Asian (SAS) AF: 0.291 AC: 17393 AN: 59810

European-Finnish (FIN) AF: 0.188 AC: 5920 AN: 31458

Middle Eastern (MID) AF: 0.214 AC: 769 AN: 3598

European-Non Finnish (NFE) AF: 0.161 AC: 90109 AN: 558054

Other (OTH) AF: 0.176 AC: 6425 AN: 36550

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

African (AFR) AF: 0.254 AC: 10544 AN: 41518

American (AMR) AF: 0.188 AC: 2881 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 574 AN: 3470

East Asian (EAS) AF: 0.155 AC: 801 AN: 5160

South Asian (SAS) AF: 0.310 AC: 1493 AN: 4822

European-Finnish (FIN) AF: 0.186 AC: 1969 AN: 10590

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11592 AN: 67960

Other (OTH) AF: 0.169 AC: 356 AN: 2106

Alfa AF: 0.198 Hom.: 424

Bravo AF: 0.196

Asia WGS AF: 0.216 AC: 753 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	-0.75
CADD	Benign	2.2
DANN	Benign	0.96
PhyloP100		-1.2
PromoterAI		-0.098	Neutral
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: rs2251780; hg19: chr8-30584923; COSMIC: COSV107279642; COSMIC: COSV107279642;