Genetic Variant NM_000637.5:c.1420-39_1420-38dupAA (chr8-30679706-C-CTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000637.5(GSR):c.1420-39_1420-38dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000074 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GSR
NM_000637.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.33

Publications

1 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

GSR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSR	NM_000637.5	MANE Select	c.1420-39_1420-38dupAA	intron	N/A	NP_000628.2	P00390-1
GSR	NM_001195102.3		c.1333-39_1333-38dupAA	intron	N/A	NP_001182031.1	P00390-3
GSR	NM_001195103.3		c.1261-39_1261-38dupAA	intron	N/A	NP_001182032.1	P00390-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSR	ENST00000221130.11	TSL:1 MANE Select	c.1420-38_1420-37insAA	intron	N/A	ENSP00000221130.5	P00390-1
GSR	ENST00000546342.5	TSL:1	c.1333-38_1333-37insAA	intron	N/A	ENSP00000445516.1	P00390-3
GSR	ENST00000541648.5	TSL:1	c.1261-38_1261-37insAA	intron	N/A	ENSP00000444559.1	P00390-4

Frequencies

GnomAD3 genomes

AF:

0.00000741

AC:

AN:

134862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000160

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000300

AC:

351

AN:

1170262

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

176

AN XY:

587378

show subpopulations

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

African (AFR)

AF:

0.000777

AC:

AN:

27020

American (AMR)

AF:

0.000355

AC:

AN:

33810

Ashkenazi Jewish (ASJ)

AF:

0.0000910

AC:

AN:

21972

East Asian (EAS)

AF:

0.000154

AC:

AN:

32370

South Asian (SAS)

AF:

0.000200

AC:

AN:

74844

European-Finnish (FIN)

AF:

0.000130

AC:

AN:

38326

Middle Eastern (MID)

AF:

0.000283

AC:

AN:

3534

European-Non Finnish (NFE)

AF:

0.000316

AC:

281

AN:

889412

Other (OTH)

AF:

0.000184

AC:

AN:

48974

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000741

AC:

AN:

134862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37082

American (AMR)

AF:

0.00

AC:

AN:

13170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3220

East Asian (EAS)

AF:

0.00

AC:

AN:

4576

South Asian (SAS)

AF:

0.00

AC:

AN:

4146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0000160

AC:

AN:

62376

Other (OTH)

AF:

0.00

AC:

AN:

1842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over