8-30680930-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000637.5(GSR):c.1393A>G(p.Met465Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GSR NM_000637.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32277718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSR	NM_000637.5	c.1393A>G	p.Met465Val	missense_variant	12/13	ENST00000221130.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSR	ENST00000221130.11	c.1393A>G	p.Met465Val	missense_variant	12/13	1	NM_000637.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461526 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.1393A>G (p.M465V) alteration is located in exon 12 (coding exon 12) of the GSR gene. This alteration results from a A to G substitution at nucleotide position 1393, causing the methionine (M) at amino acid position 465 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Uncertain	0.42	T;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	-0.13	N;.;.;.
MutationTaster	Benign	0.77	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.023	D;D;D;D
Sift4G	Uncertain	0.052	T;D;D;T
Polyphen		0.047	B;.;.;.
Vest4		0.29
MutPred		0.63		Loss of catalytic residue at M465 (P = 0.0064);.;.;.;
MVP		0.89
MPC		0.33
ClinPred		0.73	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.34
gMVP		0.78

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: rs1802931299; hg19: chr8-30538447;