rs3170633

Positions:

• chr1-93885772-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002061.4(GCLM):​c.*3218G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 152,014 control chromosomes in the GnomAD database, including 16,897 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 0.44 (16897 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCLM NM_002061.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLM	NM_002061.4	c.*3218G>A		3_prime_UTR_variant	7/7	ENST00000370238.8
GCLM	NM_001308253.2	c.*3218G>A		3_prime_UTR_variant	6/6
GCLM	XM_011541261.3	c.*3218G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLM	ENST00000370238.8	c.*3218G>A		3_prime_UTR_variant	7/7	1	NM_002061.4	P1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67502 AN: 151896 Hom.: 16862 Cov.: 33

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.415

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 EAS exome AF: 0.00

GnomAD4 genome AF: 0.445 AC: 67594 AN: 152014 Hom.: 16897 Cov.: 33 AF XY: 0.442 AC XY: 32833 AN XY: 74302

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.416

Alfa AF: 0.413 Hom.: 3719

Bravo AF: 0.467

Asia WGS AF: 0.249 AC: 864 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.5
DANN	Benign	0.69
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: rs3170633; hg19: chr1-94351328;