8-30709907-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Variant links:

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)

GSR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 [Likely_benign]. Clinvar id 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSR	NM_000637.5 link	c.334-5T>A		splice_region_variant, intron_variant	Intron 2 of 12	ENST00000221130.11	NP_000628.2	P00390-1V9HW90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSR	ENST00000221130.11 link	c.334-5T>A		splice_region_variant, intron_variant	Intron 2 of 12	1	NM_000637.5	ENSP00000221130.5		P00390-1

Frequencies

GnomAD3 genomes

AF:

0.00943

AC:

1222

AN:

129610

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.0138

AC XY:

371

AN XY:

26890

show subpopulations

⚠️ 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:

AN:

1520

Ashkenazi Jewish (ASJ)

AF:

0.00238

AC:

AN:

840

East Asian (EAS)

AF:

0.00352

AC:

AN:

1136

South Asian (SAS)

AF:

0.00144

AC:

AN:

4160

European-Finnish (FIN)

AF:

0.00230

AC:

AN:

1306

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.00600

AC:

244

AN:

40666

Other (OTH)

AF:

0.0296

AC:

AN:

2026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.376

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00947

AC:

1228

AN:

129608

Hom.:

Cov.:

AF XY:

0.00903

AC XY:

567

AN XY:

62794

show subpopulations

African (AFR)

AF:

0.0370

AC:

1136

AN:

30706

American (AMR)

AF:

0.00571

AC:

AN:

12792

Ashkenazi Jewish (ASJ)

AF:

0.000310

AC:

AN:

3230

East Asian (EAS)

AF:

0.00

AC:

AN:

4532

South Asian (SAS)

AF:

0.000476

AC:

AN:

4204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.0000797

AC:

AN:

62774

Other (OTH)

AF:

0.00629

AC:

AN:

1748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GSR-related disorder

Benign:1

May 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.7

(source)

DANN

Benign

0.24

PhyloP100

-0.62

RBP_binding_hub_radar

0.77

RBP_regulation_power_radar

3.0

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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8-30709907-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over