Genetic Variant NM_001498.4:c.1703-19G>T (chr6-53498986-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001498.4(GCLC):c.1703-19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,387,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GCLC
NM_001498.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.79

Variant links:

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 links:

GCLC-AS1 (HGNC:56649): (GCLC antisense RNA 1)

GCLC-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4 link	c.1703-19G>T		intron_variant	Intron 15 of 15	ENST00000650454.1	NP_001489.1	P48506Q14TF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1 link	c.1703-19G>T		intron_variant	Intron 15 of 15		NM_001498.4	ENSP00000497574.1		P48506

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148242

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000223

AC:

AN:

228528

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

123916

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000369

Gnomad ASJ exome

AF:

0.000323

Gnomad EAS exome

AF:

0.000244

Gnomad SAS exome

AF:

0.000190

Gnomad FIN exome

AF:

0.0000941

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000371

GnomAD4 exome

AF:

0.000100

AC:

139

AN:

1387392

Hom.:

Cov.:

AF XY:

0.0000996

AC XY:

AN XY:

693078

show subpopulations

Gnomad4 AFR exome

AF:

0.000712

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000417

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000202

AC:

AN:

148242

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72052

show subpopulations

Gnomad4 AFR

AF:

0.0000249

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000298

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000577

Hom.:

168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.47

DANN

Benign

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over