NM_001498.4:c.151-10645G>C

Variant names:

• chr6-53533172-C-G
• rs6933870
• NM_001498.4:c.151-10645G>C

Variant summary

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

The NM_001498.4(GCLC):​c.151-10645G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 152,054 control chromosomes in the GnomAD database, including 18,113 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 0.49 (18113 hom., cov: 32)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.123
• 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 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.565 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.151-10645G>C		intron	N/A	NP_001489.1
	GCLC	NM_001197115.2		c.151-10645G>C		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.151-10645G>C		intron	N/A	ENSP00000497574.1
	GCLC	ENST00000616923.5	TSL:1	c.-9-10645G>C		intron	N/A	ENSP00000482756.2
	GCLC	ENST00000514004.5	TSL:1	c.151-10645G>C		intron	N/A	ENSP00000421908.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73859 AN: 151936 Hom.: 18091 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.486 AC: 73927 AN: 152054 Hom.: 18113 Cov.: 32 AF XY: 0.489 AC XY: 36363 AN XY: 74354

African (AFR) AF: 0.510 AC: 21170 AN: 41484

American (AMR) AF: 0.576 AC: 8793 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1359 AN: 3464

East Asian (EAS) AF: 0.421 AC: 2179 AN: 5176

South Asian (SAS) AF: 0.528 AC: 2548 AN: 4822

European-Finnish (FIN) AF: 0.453 AC: 4793 AN: 10574

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31493 AN: 67940

Other (OTH) AF: 0.489 AC: 1033 AN: 2114

Alfa AF: 0.462 Hom.: 1951

Bravo AF: 0.497

Asia WGS AF: 0.474 AC: 1648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.39
PhyloP100		-0.12
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: rs6933870; hg19: chr6-53397970;