6-53498986-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001498.4(GCLC):c.1703-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,534,954 control chromosomes in the GnomAD database, including 9,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (973 hom., cov: 31)
  • Exomes 𝑓: 0.11 (8527 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.79

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-53498986-C-T is Benign according to our data. Variant chr6-53498986-C-T is described in ClinVar as [Benign]. Clinvar id is 995642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4	c.1703-19G>A		intron_variant		ENST00000650454.1
GCLC-AS1	NR_183318.1	n.327-7168C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1	c.1703-19G>A		intron_variant			NM_001498.4	P1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 16788 AN: 148200 Hom.: 971 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.00862

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0903

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.107 AC: 24558 AN: 228528 Hom.: 1400 AF XY: 0.112 AC XY: 13823 AN XY: 123916

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0593

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0103

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.108 AC: 149715 AN: 1386642 Hom.: 8527 Cov.: 24 AF XY: 0.109 AC XY: 75798 AN XY: 692770

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.0631

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.00562

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.113 AC: 16790 AN: 148312 Hom.: 973 Cov.: 31 AF XY: 0.114 AC XY: 8225 AN XY: 72142

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0847

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.00864

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.114

Alfa AF: 0.107 Hom.: 168

Bravo AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.3
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17885800; hg19: chr6-53363784;