8-30679706-CTTTTTT-CTTTT

Variant names:

• chr8-30679706-CTT-C
• rs10715710
• NM_000637.5:c.1420-39_1420-38delAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000637.5(GSR):​c.1420-39_1420-38delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,213,742 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 0)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: GSR NM_000637.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.48
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the EAS (0.187) population. However there is too low homozygotes in high coverage region: (expected more than 4546, got 1).
• BP6: Variant 8-30679706-CTT-C is Benign according to our data. Variant chr8-30679706-CTT-C is described in ClinVar as Benign. ClinVar VariationId is 1286961.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1420-39_1420-38delAA		intron	N/A	NP_000628.2	P00390-1
	GSR	NM_001195102.3		c.1333-39_1333-38delAA		intron	N/A	NP_001182031.1	P00390-3
	GSR	NM_001195103.3		c.1261-39_1261-38delAA		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.1420-39_1420-38delAA		intron	N/A	ENSP00000221130.5	P00390-1
	GSR	ENST00000546342.5	TSL:1	c.1333-39_1333-38delAA		intron	N/A	ENSP00000445516.1	P00390-3
	GSR	ENST00000541648.5	TSL:1	c.1261-39_1261-38delAA		intron	N/A	ENSP00000444559.1	P00390-4

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 274 AN: 134800 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.000932

Gnomad EAS AF: 0.00109

Gnomad SAS AF: 0.000240

Gnomad FIN AF: 0.00875

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00133

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.183 AC: 24102 AN: 131578 AF XY: 0.185

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.137 AC: 148300 AN: 1078942 Hom.: 0 AF XY: 0.138 AC XY: 74381 AN XY: 538252

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

African (AFR) AF: 0.0949 AC: 2423 AN: 25522

American (AMR) AF: 0.167 AC: 4898 AN: 29294

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 3348 AN: 19238

East Asian (EAS) AF: 0.191 AC: 5434 AN: 28412

South Asian (SAS) AF: 0.132 AC: 8587 AN: 65158

European-Finnish (FIN) AF: 0.145 AC: 5019 AN: 34726

Middle Eastern (MID) AF: 0.143 AC: 461 AN: 3230

European-Non Finnish (NFE) AF: 0.135 AC: 111711 AN: 828572

Other (OTH) AF: 0.143 AC: 6419 AN: 44790

⚠️ 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: 0.00204 AC: 275 AN: 134800 Hom.: 1 Cov.: 0 AF XY: 0.00239 AC XY: 155 AN XY: 64878

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

African (AFR) AF: 0.00197 AC: 73 AN: 37082

American (AMR) AF: 0.00296 AC: 39 AN: 13168

Ashkenazi Jewish (ASJ) AF: 0.000932 AC: 3 AN: 3218

East Asian (EAS) AF: 0.00109 AC: 5 AN: 4576

South Asian (SAS) AF: 0.000241 AC: 1 AN: 4146

European-Finnish (FIN) AF: 0.00875 AC: 64 AN: 7314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00133 AC: 83 AN: 62340

Other (OTH) AF: 0.00380 AC: 7 AN: 1840

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.105 Hom.: 959

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs10715710; hg19: chr8-30537223;