6-53507347-T-C

Variant names:

• chr6-53507347-T-C
• rs1555903
• NM_001498.4:c.1084+133A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001498.4(GCLC):​c.1084+133A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 854,782 control chromosomes in the GnomAD database, including 16,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3779 hom., cov: 32)
  • Exomes 𝑓: 0.14 (12805 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0690
• Publications: 11 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-AS1 (HGNC:56649): (GCLC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-53507347-T-C is Benign according to our data. Variant chr6-53507347-T-C is described in ClinVar as Benign. ClinVar VariationId is 1261932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLC	NM_001498.4	c.1084+133A>G		intron_variant	Intron 9 of 15	ENST00000650454.1	NP_001489.1
GCLC	NM_001197115.2	c.970+133A>G		intron_variant	Intron 8 of 14		NP_001184044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLC	ENST00000650454.1	c.1084+133A>G		intron_variant	Intron 9 of 15		NM_001498.4	ENSP00000497574.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27976 AN: 151956 Hom.: 3761 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.142 AC: 99818 AN: 702706 Hom.: 12805 AF XY: 0.141 AC XY: 53023 AN XY: 375436

African (AFR) AF: 0.286 AC: 5027 AN: 17556

American (AMR) AF: 0.491 AC: 16456 AN: 33482

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2028 AN: 19606

East Asian (EAS) AF: 0.451 AC: 16189 AN: 35928

South Asian (SAS) AF: 0.219 AC: 14046 AN: 64098

European-Finnish (FIN) AF: 0.0990 AC: 3917 AN: 39560

Middle Eastern (MID) AF: 0.209 AC: 870 AN: 4172

European-Non Finnish (NFE) AF: 0.0795 AC: 36014 AN: 453080

Other (OTH) AF: 0.150 AC: 5271 AN: 35224

GnomAD4 genome AF: 0.184 AC: 28048 AN: 152076 Hom.: 3779 Cov.: 32 AF XY: 0.192 AC XY: 14247 AN XY: 74330

African (AFR) AF: 0.283 AC: 11739 AN: 41442

American (AMR) AF: 0.362 AC: 5528 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2267 AN: 5180

South Asian (SAS) AF: 0.237 AC: 1145 AN: 4822

European-Finnish (FIN) AF: 0.101 AC: 1063 AN: 10570

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.0800 AC: 5440 AN: 67990

Other (OTH) AF: 0.181 AC: 382 AN: 2112

Alfa AF: 0.143 Hom.: 1865

Bravo AF: 0.211

Asia WGS AF: 0.311 AC: 1078 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		-0.069
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: rs1555903; hg19: chr6-53372145;