rs718873

chr1-93906353-T-Cchr1-93906353-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002061.4(GCLM):c.127-1765A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,092 control chromosomes in the GnomAD database, including 2,647 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2647 hom., cov: 32)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199

Genes affected

GCLM (HGNC:4312): (glutamate-cysteine ligase modifier subunit) Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase, is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLM	NM_002061.4	c.127-1765A>G		intron_variant		ENST00000370238.8
GCLM	NM_001308253.2	c.126+2685A>G		intron_variant
GCLM	XM_011541261.3	c.-138-1765A>G		intron_variant
GCLM	XM_047418031.1	c.127-1765A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLM	ENST00000370238.8	c.127-1765A>G		intron_variant		1	NM_002061.4	P1
GCLM	ENST00000615724.1	c.126+2685A>G		intron_variant		1
GCLM	ENST00000462183.1	n.261-1765A>G		intron_variant, non_coding_transcript_variant		3
GCLM	ENST00000467772.1	n.127-1765A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27504 AN: 151974 Hom.: 2639 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.191

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.181 AC: 27536 AN: 152092 Hom.: 2647 Cov.: 32 AF XY: 0.181 AC XY: 13417 AN XY: 74332

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.161

Gnomad4 SAS AF: 0.0936

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.189

Alfa AF: 0.177 Hom.: 2682

Bravo AF: 0.198

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.7
Dann	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs718873; hg19: chr1-94371909;