rs3736729

Positions:

• chr6-53514607-A-C

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.561-110T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 817,086 control chromosomes in the GnomAD database, including 92,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15500 hom., cov: 32)
  • Exomes 𝑓: 0.48 (76994 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-53514607-A-C is Benign according to our data. Variant chr6-53514607-A-C is described in ClinVar as [Benign]. Clinvar id is 1274104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4	c.561-110T>G		intron_variant		ENST00000650454.1
GCLC	NM_001197115.2	c.447-110T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1	c.561-110T>G		intron_variant			NM_001498.4	P1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67728 AN: 151952 Hom.: 15485 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.477 AC: 317174 AN: 665014 Hom.: 76994 AF XY: 0.478 AC XY: 171577 AN XY: 358992

Gnomad4 AFR exome AF: 0.355

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.519

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.446 AC: 67768 AN: 152072 Hom.: 15500 Cov.: 32 AF XY: 0.449 AC XY: 33385 AN XY: 74358

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.528

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.460

Alfa AF: 0.470 Hom.: 16657

Bravo AF: 0.450

Asia WGS AF: 0.469 AC: 1630 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

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3736729; hg19: chr6-53379405; COSMIC: COSV57597419; COSMIC: COSV57597419;