rs1014852

Positions:

• chr6-53505954-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001498.4(GCLC):​c.1198-59T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 920,932 control chromosomes in the GnomAD database, including 19,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (4576 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14539 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.80

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:56649): (GCLC antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-53505954-A-T is Benign according to our data. Variant chr6-53505954-A-T is described in ClinVar as [Benign]. Clinvar id is 1251336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1198-59T>A		intron_variant		ENST00000650454.1	NP_001489.1
GCLC-AS1	NR_183318.1	n.327-200A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1198-59T>A		intron_variant			NM_001498.4	ENSP00000497574	P1
GCLC-AS1	ENST00000655377.1	n.212-200A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29194 AN: 152042 Hom.: 4554 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.0639

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0956

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.133 AC: 102023 AN: 768772 Hom.: 14539 Cov.: 10 AF XY: 0.130 AC XY: 53268 AN XY: 410038

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.450

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.0968

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.192 AC: 29276 AN: 152160 Hom.: 4576 Cov.: 32 AF XY: 0.199 AC XY: 14817 AN XY: 74378

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.0639

Gnomad4 EAS AF: 0.436

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.0956

Gnomad4 NFE AF: 0.0596

Gnomad4 OTH AF: 0.166

Alfa AF: 0.127 Hom.: 347

Bravo AF: 0.222

Asia WGS AF: 0.310 AC: 1075 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.0
DANN	Benign	0.71

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: rs1014852; hg19: chr6-53370752;