rs761141

Variant names:

• chr6-53520545-C-T
• rs761141
• NM_001498.4:c.446+233G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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-AS1 (HGNC:56649): (GCLC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	NM_001498.4	MANE Select	c.446+233G>A		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.446+233G>A		intron	N/A	NP_001184044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.446+233G>A		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.287+233G>A		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000514004.5	TSL:1	c.446+233G>A		intron	N/A	ENSP00000421908.1

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

African (AFR) AF: 0.173 AC: 7175 AN: 41538

American (AMR) AF: 0.139 AC: 2128 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3466

East Asian (EAS) AF: 0.134 AC: 695 AN: 5180

South Asian (SAS) AF: 0.136 AC: 658 AN: 4824

European-Finnish (FIN) AF: 0.243 AC: 2573 AN: 10588

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15981 AN: 67960

Other (OTH) AF: 0.190 AC: 402 AN: 2114

Alfa AF: 0.220 Hom.: 6430

Bravo AF: 0.192

Asia WGS AF: 0.126 AC: 438 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.67
PhyloP100		1.6
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: rs761141; hg19: chr6-53385343; COSMIC: COSV57594163; COSMIC: COSV57594163;