6-53527310-A-C

Variant names:

• chr6-53527310-A-C
• rs761142
• NM_001498.4:c.151-4783T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001498.4(GCLC):​c.151-4783T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 152,026 control chromosomes in the GnomAD database, including 8,823 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8823 hom., cov: 32)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 14 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 Gene-Disease associations (from GenCC):

• gamma-glutamylcysteine synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.447 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.151-4783T>G		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.151-4783T>G		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.151-4783T>G		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.-9-4783T>G		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000514004.5	TSL:1	c.151-4783T>G		intron	N/A	ENSP00000421908.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50780 AN: 151908 Hom.: 8808 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.334 AC: 50840 AN: 152026 Hom.: 8823 Cov.: 32 AF XY: 0.338 AC XY: 25147 AN XY: 74310

African (AFR) AF: 0.376 AC: 15584 AN: 41432

American (AMR) AF: 0.456 AC: 6958 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 915 AN: 3472

East Asian (EAS) AF: 0.397 AC: 2048 AN: 5162

South Asian (SAS) AF: 0.360 AC: 1734 AN: 4814

European-Finnish (FIN) AF: 0.275 AC: 2907 AN: 10584

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19635 AN: 67980

Other (OTH) AF: 0.336 AC: 708 AN: 2106

Alfa AF: 0.316 Hom.: 4931

Bravo AF: 0.351

Asia WGS AF: 0.358 AC: 1242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.6
DANN	Benign	0.84
PhyloP100		-0.39
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: rs761142; hg19: chr6-53392108; COSMIC: COSV57594748; COSMIC: COSV57594748;