rs769211

chr1-93894551-C-A

Variant summary

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

The NM_002061.4(GCLM):c.655+63G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 885,808 control chromosomes in the GnomAD database, including 29,253 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 0.26 (5188 hom., cov: 32)
  • Exomes 𝑓: 0.25 (24065 hom.)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500

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=-0.53).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLM	NM_002061.4	c.655+63G>T		intron_variant		ENST00000370238.8
GCLM	NM_001308253.2	c.589+63G>T		intron_variant
GCLM	XM_011541261.3	c.391+63G>T		intron_variant
GCLM	XM_047418031.1	c.655+63G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLM	ENST00000370238.8	c.655+63G>T		intron_variant		1	NM_002061.4	P1
GCLM	ENST00000615724.1	c.589+63G>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39246 AN: 151878 Hom.: 5183 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.249 AC: 182852 AN: 733812 Hom.: 24065 AF XY: 0.241 AC XY: 94184 AN XY: 390012

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.258 AC: 39268 AN: 151996 Hom.: 5188 Cov.: 32 AF XY: 0.258 AC XY: 19198 AN XY: 74276

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.251

Alfa AF: 0.265 Hom.: 6359

Bravo AF: 0.270

Asia WGS AF: 0.144 AC: 497 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	3.1
Dann	Benign	0.46

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: rs769211; hg19: chr1-94360107;