6-53498978-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001498.4(GCLC):c.1703-11C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,581,032 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (97 hom.)
• Consequence: GCLC NM_001498.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002752
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 6-53498978-G-C is Benign according to our data. Variant chr6-53498978-G-C is described in ClinVar as [Benign]. Clinvar id is 811041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLC	NM_001498.4	c.1703-11C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000650454.1
GCLC-AS1	NR_183318.1	n.327-7176G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLC	ENST00000650454.1	c.1703-11C>G		splice_polypyrimidine_tract_variant, intron_variant			NM_001498.4	P1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 411 AN: 151226 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.0000972

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00603 AC: 1478 AN: 245266 Hom.: 51 AF XY: 0.00554 AC XY: 735 AN XY: 132656

Gnomad AFR exome AF: 0.000868

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000807

Gnomad EAS exome AF: 0.0741

Gnomad SAS exome AF: 0.00191

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00230 AC: 3292 AN: 1429688 Hom.: 97 Cov.: 27 AF XY: 0.00226 AC XY: 1613 AN XY: 712754

Gnomad4 AFR exome AF: 0.000367

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.000775

Gnomad4 EAS exome AF: 0.0638

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.00483

GnomAD4 genome AF: 0.00272 AC: 411 AN: 151344 Hom.: 10 Cov.: 32 AF XY: 0.00286 AC XY: 211 AN XY: 73888

Gnomad4 AFR AF: 0.000533

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.0643

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.0000972

Gnomad4 NFE AF: 0.000295

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000898 Hom.: 2

Bravo AF: 0.00321

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 14, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.021
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.040
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

Other links and lift over

dbSNP: rs2066507; hg19: chr6-53363776;