rs761141

Positions:

• chr6-53520545-C-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.446+233G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 152,168 control chromosomes in the GnomAD database, including 3,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.20 (3130 hom., cov: 32)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57

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=-0.84).
• BP6: Variant 6-53520545-C-T is Benign according to our data. Variant chr6-53520545-C-T is described in ClinVar as [Benign]. Clinvar id is 1230674.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLC	NM_001498.4	c.446+233G>A		intron_variant		ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.446+233G>A		intron_variant			NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.446+233G>A		intron_variant			NM_001498.4	ENSP00000497574	P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30444 AN: 152050 Hom.: 3128 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.200 AC: 30443 AN: 152168 Hom.: 3130 Cov.: 32 AF XY: 0.197 AC XY: 14684 AN XY: 74384

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.190

Alfa AF: 0.223 Hom.: 5230

Bravo AF: 0.192

Asia WGS AF: 0.126 AC: 438 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	-0.84
CADD	Benign	6.1
DANN	Benign	0.67

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: rs761141; hg19: chr6-53385343; COSMIC: COSV57594163; COSMIC: COSV57594163;