6-53543991-A-G

Variant names:

• chr6-53543991-A-G
• rs510088
• NM_001498.4:c.150+505T>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.150+505T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 152,066 control chromosomes in the GnomAD database, including 42,331 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 0.74 (42331 hom., cov: 32)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.933
• Publications: 8 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, Orphanet, Labcorp Genetics (formerly Invitae)
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.894 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.150+505T>C		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.150+505T>C		intron	N/A	NP_001184044.1	E1CEI4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.150+505T>C		intron	N/A	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.-10+4065T>C		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000514004.5	TSL:1	c.150+505T>C		intron	N/A	ENSP00000421908.1	A0A0C4DGB2

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112934 AN: 151948 Hom.: 42272 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.730

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

GnomAD4 genome AF: 0.743 AC: 113053 AN: 152066 Hom.: 42331 Cov.: 32 AF XY: 0.742 AC XY: 55115 AN XY: 74322

African (AFR) AF: 0.820 AC: 34025 AN: 41498

American (AMR) AF: 0.790 AC: 12066 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2322 AN: 3470

East Asian (EAS) AF: 0.915 AC: 4732 AN: 5170

South Asian (SAS) AF: 0.752 AC: 3629 AN: 4824

European-Finnish (FIN) AF: 0.644 AC: 6793 AN: 10550

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47179 AN: 67968

Other (OTH) AF: 0.734 AC: 1547 AN: 2108

Alfa AF: 0.707 Hom.: 63535

Bravo AF: 0.757

Asia WGS AF: 0.830 AC: 2889 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-0.93
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: rs510088; hg19: chr6-53408789;