rs743119

Positions:

• chr1-93909186-C-A

Variant summary

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

The ENST00000370238.8(GCLM):​c.-23G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,229,094 control chromosomes in the GnomAD database, including 25,370 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 (6645 hom., cov: 32)
  • Exomes 𝑓: 0.18 (18725 hom.)
• Consequence: GCLM ENST00000370238.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205

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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLM	NM_002061.4	c.-23G>T		5_prime_UTR_variant	1/7	ENST00000370238.8	NP_002052.1
GCLM	NM_001308253.2	c.-23G>T		5_prime_UTR_variant	1/6		NP_001295182.1
GCLM	XM_047418031.1	c.-23G>T		5_prime_UTR_variant	1/7		XP_047273987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLM	ENST00000370238.8	c.-23G>T		5_prime_UTR_variant	1/7	1	NM_002061.4	ENSP00000359258	P1
GCLM	ENST00000615724.1	c.-23G>T		5_prime_UTR_variant	1/6	1		ENSP00000484507

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39501 AN: 151002 Hom.: 6624 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.248

GnomAD3 exomes AF: 0.351 AC: 1082 AN: 3082 Hom.: 206 AF XY: 0.323 AC XY: 683 AN XY: 2116

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.634

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.559

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.178 AC: 191889 AN: 1077982 Hom.: 18725 Cov.: 31 AF XY: 0.176 AC XY: 91293 AN XY: 517260

Gnomad4 AFR exome AF: 0.494

Gnomad4 AMR exome AF: 0.351

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.262 AC: 39560 AN: 151112 Hom.: 6645 Cov.: 32 AF XY: 0.259 AC XY: 19117 AN XY: 73870

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.0954

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.246

Alfa AF: 0.223 Hom.: 624

Bravo AF: 0.290

Asia WGS AF: 0.139 AC: 471 AN: 3396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs743119; hg19: chr1-94374742;