rs1014852

Variant names:

• chr6-53505954-A-T
• rs1014852
• NM_001498.4:c.1198-59T>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.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
• Publications: 6 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=-0.85).
• BP6: Variant 6-53505954-A-T is Benign according to our data. Variant chr6-53505954-A-T is described in ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	NM_001498.4	MANE Select	c.1198-59T>A		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.1084-59T>A		intron	N/A	NP_001184044.1
	GCLC-AS1	NR_183318.1		n.327-200A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1198-59T>A		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.1039-59T>A		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000643939.1		c.1204-59T>A		intron	N/A	ENSP00000495686.1

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

African (AFR) AF: 0.368 AC: 7505 AN: 20374

American (AMR) AF: 0.497 AC: 21757 AN: 43788

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1647 AN: 21832

East Asian (EAS) AF: 0.450 AC: 16462 AN: 36568

South Asian (SAS) AF: 0.208 AC: 15048 AN: 72442

European-Finnish (FIN) AF: 0.0968 AC: 5117 AN: 52852

Middle Eastern (MID) AF: 0.143 AC: 621 AN: 4352

European-Non Finnish (NFE) AF: 0.0597 AC: 28589 AN: 478838

Other (OTH) AF: 0.140 AC: 5277 AN: 37726

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

African (AFR) AF: 0.357 AC: 14806 AN: 41476

American (AMR) AF: 0.349 AC: 5339 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 222 AN: 3472

East Asian (EAS) AF: 0.436 AC: 2257 AN: 5172

South Asian (SAS) AF: 0.227 AC: 1093 AN: 4820

European-Finnish (FIN) AF: 0.0956 AC: 1014 AN: 10602

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0596 AC: 4052 AN: 68018

Other (OTH) AF: 0.166 AC: 351 AN: 2112

Alfa AF: 0.127 Hom.: 347

Bravo AF: 0.222

Asia WGS AF: 0.310 AC: 1075 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	-0.85
CADD	Benign	6.0
DANN	Benign	0.71
PhyloP100		1.8
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: rs1014852; hg19: chr6-53370752;