6-53533761-C-T

Variant names:

• chr6-53533761-C-T
• rs502862
• NM_001498.4:c.150+10735G>A

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+10735G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 151,178 control chromosomes in the GnomAD database, including 30,774 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 0.63 (30774 hom., cov: 30)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 7 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.150+10735G>A		intron_variant	Intron 1 of 15	ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.150+10735G>A		intron_variant	Intron 1 of 14		NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.150+10735G>A		intron_variant	Intron 1 of 15		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 95646 AN: 151066 Hom.: 30730 Cov.: 30

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.622

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.633 AC: 95745 AN: 151178 Hom.: 30774 Cov.: 30 AF XY: 0.639 AC XY: 47124 AN XY: 73804

African (AFR) AF: 0.726 AC: 29924 AN: 41222

American (AMR) AF: 0.663 AC: 10078 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1673 AN: 3464

East Asian (EAS) AF: 0.682 AC: 3514 AN: 5156

South Asian (SAS) AF: 0.713 AC: 3430 AN: 4808

European-Finnish (FIN) AF: 0.646 AC: 6582 AN: 10184

Middle Eastern (MID) AF: 0.628 AC: 181 AN: 288

European-Non Finnish (NFE) AF: 0.569 AC: 38619 AN: 67846

Other (OTH) AF: 0.604 AC: 1268 AN: 2098

Alfa AF: 0.594 Hom.: 57633

Bravo AF: 0.637

Asia WGS AF: 0.700 AC: 2434 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.024
DANN	Benign	0.57
PhyloP100		-2.4
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: rs502862; hg19: chr6-53398559;