rs534957

Variant names:

• chr6-53541553-G-C
• rs534957
• NM_001498.4:c.150+2943C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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]

GCLC Gene-Disease associations (from GenCC):

• gamma-glutamylcysteine synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	NM_001498.4	MANE Select	c.150+2943C>G		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.150+2943C>G		intron	N/A	NP_001184044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.150+2943C>G		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.-10+6503C>G		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000514004.5	TSL:1	c.150+2943C>G		intron	N/A	ENSP00000421908.1

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

African (AFR) AF: 0.544 AC: 22487 AN: 41338

American (AMR) AF: 0.322 AC: 4891 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1252 AN: 3456

East Asian (EAS) AF: 0.360 AC: 1808 AN: 5026

South Asian (SAS) AF: 0.396 AC: 1863 AN: 4710

European-Finnish (FIN) AF: 0.285 AC: 2940 AN: 10328

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.337 AC: 22847 AN: 67718

Other (OTH) AF: 0.376 AC: 792 AN: 2106

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.0
DANN	Benign	0.59
PhyloP100		-0.10
Mutation Taster		=100/0	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: rs534957; hg19: chr6-53406351;