Genetic Variant GCLM:c.655+63G>T (chr1-93894551-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002061.4(GCLM):c.655+63G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 885,808 control chromosomes in the GnomAD database, including 29,253 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 0.26 ( 5188 hom., cov: 32)

Exomes 𝑓: 0.25 ( 24065 hom. )

Consequence

GCLM
NM_002061.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0500

Publications

10 publications found

Variant links:

Genes affected

GCLM (HGNC:4312): (glutamate-cysteine ligase modifier 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. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

GCLM links:

ENSG00000310419 (HGNC:):

ENSG00000310419 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GCLM	NM_002061.4 link	c.655+63G>T	intron_variant	Intron 6 of 6	ENST00000370238.8	NP_002052.1
GCLM	NM_001308253.2 link	c.589+63G>T	intron_variant	Intron 5 of 5		NP_001295182.1
GCLM	XM_047418031.1 link	c.655+63G>T	intron_variant	Intron 6 of 6		XP_047273987.1
GCLM	XM_011541261.3 link	c.391+63G>T	intron_variant	Intron 6 of 6		XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GCLM	ENST00000370238.8 link	c.655+63G>T	intron_variant	Intron 6 of 6	1	NM_002061.4	ENSP00000359258.3
GCLM	ENST00000615724.1 link	c.589+63G>T	intron_variant	Intron 5 of 5	1		ENSP00000484507.1
ENSG00000310419	ENST00000849663.1 link	n.402-7064C>A	intron_variant	Intron 3 of 3
GCLM	ENST00000467772.1 link	n.*93G>T	downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39246

AN:

151878

Hom.:

5183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.250

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.348

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.253

GnomAD4 exome

AF:

0.249

AC:

182852

AN:

733812

Hom.:

24065

AF XY:

0.241

AC XY:

94184

AN XY:

390012

show subpopulations

African (AFR)

AF:

0.244

AC:

4622

AN:

18942

American (AMR)

AF:

0.377

AC:

14565

AN:

38592

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

4680

AN:

20350

East Asian (EAS)

AF:

0.154

AC:

5550

AN:

35956

South Asian (SAS)

AF:

0.117

AC:

7946

AN:

67912

European-Finnish (FIN)

AF:

0.239

AC:

12028

AN:

50414

Middle Eastern (MID)

AF:

0.194

AC:

781

AN:

4034

European-Non Finnish (NFE)

AF:

0.268

AC:

123843

AN:

461678

Other (OTH)

AF:

0.246

AC:

8837

AN:

35934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

6404

12807

19211

25614

32018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2280

4560

6840

9120

11400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.258

AC:

39268

AN:

151996

Hom.:

5188

Cov.:

AF XY:

0.258

AC XY:

19198

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.250

AC:

10368

AN:

41452

American (AMR)

AF:

0.348

AC:

5312

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

788

AN:

3470

East Asian (EAS)

AF:

0.165

AC:

851

AN:

5172

South Asian (SAS)

AF:

0.115

AC:

556

AN:

4830

European-Finnish (FIN)

AF:

0.239

AC:

2513

AN:

10530

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18076

AN:

67962

Other (OTH)

AF:

0.251

AC:

529

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1466

2932

4399

5865

7331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.265

Hom.:

12260

Bravo

AF:

0.270

Asia WGS

AF:

0.144

AC:

497

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

3.1

(source)

DANN

Benign

0.46

PhyloP100

0.050

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over