8-30709907-A-T

Variant names:

• chr8-30709907-A-T
• rs28641651
• NM_000637.5:c.334-5T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000637.5(GSR):​c.334-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 183,624 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (16 hom., cov: 30)
  • Exomes 𝑓: 0.016 (2 hom.)
• Consequence: GSR NM_000637.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003841
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.622
• Publications: 0 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=-0.91).
• BP6: Variant 8-30709907-A-T is Benign according to our data. Variant chr8-30709907-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00947 (1228/129608) while in subpopulation AFR AF = 0.037 (1136/30706). AF 95% confidence interval is 0.0352. There are 16 homozygotes in GnomAd4. There are 567 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.334-5T>A		splice_region intron	N/A	NP_000628.2
	GSR	NM_001195102.3		c.334-5T>A		splice_region intron	N/A	NP_001182031.1
	GSR	NM_001195103.3		c.334-5T>A		splice_region 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.334-5T>A		splice_region intron	N/A	ENSP00000221130.5
	GSR	ENST00000546342.5	TSL:1	c.334-5T>A		splice_region intron	N/A	ENSP00000445516.1
	GSR	ENST00000541648.5	TSL:1	c.334-5T>A		splice_region intron	N/A	ENSP00000444559.1

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1222 AN: 129610 Hom.: 15 Cov.: 30

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00579

Gnomad ASJ AF: 0.000310

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000475

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000796

Gnomad OTH AF: 0.00631

GnomAD2 exomes AF: 0.00729 AC: 642 AN: 88028 AF XY: 0.00469

Gnomad AFR exome AF: 0.0880

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.0156 AC: 844 AN: 54016 Hom.: 2 Cov.: 0 AF XY: 0.0138 AC XY: 371 AN XY: 26890

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.216 AC: 469 AN: 2174

American (AMR) AF: 0.0349 AC: 53 AN: 1520

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 2 AN: 840

East Asian (EAS) AF: 0.00352 AC: 4 AN: 1136

South Asian (SAS) AF: 0.00144 AC: 6 AN: 4160

European-Finnish (FIN) AF: 0.00230 AC: 3 AN: 1306

Middle Eastern (MID) AF: 0.0160 AC: 3 AN: 188

European-Non Finnish (NFE) AF: 0.00600 AC: 244 AN: 40666

Other (OTH) AF: 0.0296 AC: 60 AN: 2026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00947 AC: 1228 AN: 129608 Hom.: 16 Cov.: 30 AF XY: 0.00903 AC XY: 567 AN XY: 62794

African (AFR) AF: 0.0370 AC: 1136 AN: 30706

American (AMR) AF: 0.00571 AC: 73 AN: 12792

Ashkenazi Jewish (ASJ) AF: 0.000310 AC: 1 AN: 3230

East Asian (EAS) AF: 0.00 AC: 0 AN: 4532

South Asian (SAS) AF: 0.000476 AC: 2 AN: 4204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.0000797 AC: 5 AN: 62774

Other (OTH) AF: 0.00629 AC: 11 AN: 1748

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GSR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.24
PhyloP100		-0.62
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		3.0
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.032
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: rs28641651; hg19: chr8-30567424;