rs743119

Variant names:

• chr1-93909186-C-A
• rs743119
• NM_002061.4:c.-23G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002061.4(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 NM_002061.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002061.4. 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
	GCLM	NM_002061.4	MANE Select	c.-23G>T		5_prime_UTR	Exon 1 of 7	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.-23G>T		5_prime_UTR	Exon 1 of 6	NP_001295182.1	P48507-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLM	ENST00000370238.8	TSL:1 MANE Select	c.-23G>T		5_prime_UTR	Exon 1 of 7	ENSP00000359258.3	P48507-1
	GCLM	ENST00000615724.1	TSL:1	c.-23G>T		5_prime_UTR	Exon 1 of 6	ENSP00000484507.1	P48507-2
	GCLM	ENST00000871361.1		c.-23G>T		5_prime_UTR	Exon 1 of 8	ENSP00000541420.1

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

GnomAD2 exomes AF: 0.351 AC: 1082 AN: 3082 AF XY: 0.323

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 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

African (AFR) AF: 0.494 AC: 10852 AN: 21952

American (AMR) AF: 0.351 AC: 2691 AN: 7660

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 2213 AN: 12746

East Asian (EAS) AF: 0.165 AC: 3800 AN: 23072

South Asian (SAS) AF: 0.103 AC: 2811 AN: 27240

European-Finnish (FIN) AF: 0.128 AC: 2719 AN: 21292

Middle Eastern (MID) AF: 0.161 AC: 448 AN: 2782

European-Non Finnish (NFE) AF: 0.172 AC: 158296 AN: 919424

Other (OTH) AF: 0.193 AC: 8059 AN: 41814

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

African (AFR) AF: 0.469 AC: 19388 AN: 41350

American (AMR) AF: 0.326 AC: 4950 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3464

East Asian (EAS) AF: 0.162 AC: 827 AN: 5104

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4824

European-Finnish (FIN) AF: 0.123 AC: 1256 AN: 10210

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.169 AC: 11420 AN: 67680

Other (OTH) AF: 0.246 AC: 516 AN: 2096

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.84
PhyloP100		-0.20
PromoterAI		-0.0063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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: rs743119; hg19: chr1-94374742;