chr8-30679706-CTTT-C

Variant names:

• chr8-30679706-CTTT-C
• rs10715710
• NM_000637.5:c.1420-40_1420-38delAAA

Variant summary

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

The NM_000637.5(GSR):​c.1420-40_1420-38delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,280,356 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0072 (0 hom.)
• Consequence: GSR NM_000637.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.00747) population. However there is too low homozygotes in high coverage region: (expected more than 13, got 0).

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.1420-40_1420-38delAAA		intron	N/A	NP_000628.2	P00390-1
	GSR	NM_001195102.3		c.1333-40_1333-38delAAA		intron	N/A	NP_001182031.1	P00390-3
	GSR	NM_001195103.3		c.1261-40_1261-38delAAA		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.1420-40_1420-38delAAA		intron	N/A	ENSP00000221130.5	P00390-1
	GSR	ENST00000546342.5	TSL:1	c.1333-40_1333-38delAAA		intron	N/A	ENSP00000445516.1	P00390-3
	GSR	ENST00000541648.5	TSL:1	c.1261-40_1261-38delAAA		intron	N/A	ENSP00000444559.1	P00390-4

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 16 AN: 134836 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000128

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00746 AC: 981 AN: 131578 AF XY: 0.00753

Gnomad AFR exome AF: 0.00354

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.00564

Gnomad EAS exome AF: 0.00613

Gnomad FIN exome AF: 0.00956

Gnomad NFE exome AF: 0.00954

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00724 AC: 8295 AN: 1145520 Hom.: 0 AF XY: 0.00689 AC XY: 3960 AN XY: 575128

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

African (AFR) AF: 0.00594 AC: 158 AN: 26592

American (AMR) AF: 0.00721 AC: 239 AN: 33150

Ashkenazi Jewish (ASJ) AF: 0.00668 AC: 143 AN: 21398

East Asian (EAS) AF: 0.00687 AC: 215 AN: 31298

South Asian (SAS) AF: 0.00286 AC: 211 AN: 73720

European-Finnish (FIN) AF: 0.00817 AC: 306 AN: 37468

Middle Eastern (MID) AF: 0.00696 AC: 24 AN: 3450

European-Non Finnish (NFE) AF: 0.00762 AC: 6633 AN: 870576

Other (OTH) AF: 0.00765 AC: 366 AN: 47868

⚠️ 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: 0.000119 AC: 16 AN: 134836 Hom.: 0 Cov.: 0 AF XY: 0.000154 AC XY: 10 AN XY: 64896

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

African (AFR) AF: 0.0000539 AC: 2 AN: 37080

American (AMR) AF: 0.000152 AC: 2 AN: 13170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3220

East Asian (EAS) AF: 0.00 AC: 0 AN: 4576

South Asian (SAS) AF: 0.00 AC: 0 AN: 4146

European-Finnish (FIN) AF: 0.000546 AC: 4 AN: 7322

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

European-Non Finnish (NFE) AF: 0.000128 AC: 8 AN: 62364

Other (OTH) AF: 0.00 AC: 0 AN: 1842

⚠️ 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: 0.0111 Hom.: 959

ClinVar

Not reported in ClinVar

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;