rs534957

Positions:

• chr6-53541553-G-C

Variant summary

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

The NM_001498.4(GCLC):​c.150+2943C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 151,052 control chromosomes in the GnomAD database, including 12,256 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 0.39 (12256 hom., cov: 30)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105

Genes affected

GCLC (HGNC:4311): (glutamate-cysteine ligase catalytic 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. This locus encodes the catalytic subunit, while the regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Mutations at this locus have been associated with hemolytic anemia due to deficiency of gamma-glutamylcysteine synthetase and susceptibility to myocardial infarction.[provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLC	NM_001498.4	c.150+2943C>G		intron_variant		ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.150+2943C>G		intron_variant			NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.150+2943C>G		intron_variant			NM_001498.4	ENSP00000497574	P1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59145 AN: 150934 Hom.: 12226 Cov.: 30

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.392 AC: 59226 AN: 151052 Hom.: 12256 Cov.: 30 AF XY: 0.388 AC XY: 28645 AN XY: 73786

Gnomad4 AFR AF: 0.544

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.376

Alfa AF: 0.356 Hom.: 1280

Bravo AF: 0.403

Asia WGS AF: 0.382 AC: 1333 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.0
DANN	Benign	0.59

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: rs534957; hg19: chr6-53406351;