dbSNP rs7515191: GCLM:c.277+44C>T (chr1-93901541-G-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.277+44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 975,892 control chromosomes in the GnomAD database, including 69,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.44 ( 16906 hom., cov: 32)

Exomes 𝑓: 0.35 ( 52168 hom. )

Consequence

GCLM
NM_002061.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0810

Publications

16 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=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002061.4. 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
	GCLM	NM_002061.4	MANE Select	c.277+44C>T		intron	N/A	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.211+44C>T		intron	N/A	NP_001295182.1	P48507-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCLM	ENST00000370238.8	TSL:1 MANE Select	c.277+44C>T	intron	N/A	ENSP00000359258.3	P48507-1
GCLM	ENST00000615724.1	TSL:1	c.211+44C>T	intron	N/A	ENSP00000484507.1	P48507-2
GCLM	ENST00000871361.1		c.331+44C>T	intron	N/A	ENSP00000541420.1

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

67509

AN:

151840

Hom.:

16871

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.464

Gnomad ASJ

AF:

0.302

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.352

Gnomad MID

AF:

0.334

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.362

AC:

82965

AN:

229424

AF XY:

0.348

show subpopulations

Gnomad AFR exome

AF:

0.690

Gnomad AMR exome

AF:

0.477

Gnomad ASJ exome

AF:

0.312

Gnomad EAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.349

Gnomad NFE exome

AF:

0.349

Gnomad OTH exome

AF:

0.343

GnomAD4 exome

AF:

0.346

AC:

284685

AN:

823934

Hom.:

52168

Cov.:

AF XY:

0.339

AC XY:

147705

AN XY:

435296

show subpopulations

African (AFR)

AF:

0.691

AC:

13859

AN:

20066

American (AMR)

AF:

0.472

AC:

16730

AN:

35414

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

6792

AN:

21360

East Asian (EAS)

AF:

0.198

AC:

7267

AN:

36770

South Asian (SAS)

AF:

0.232

AC:

16107

AN:

69572

European-Finnish (FIN)

AF:

0.344

AC:

18247

AN:

52996

Middle Eastern (MID)

AF:

0.301

AC:

1280

AN:

4246

European-Non Finnish (NFE)

AF:

0.350

AC:

190627

AN:

544364

Other (OTH)

AF:

0.352

AC:

13776

AN:

39146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

9506

19012

28517

38023

47529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3812

7624

11436

15248

19060

<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:

0.445

AC:

67600

AN:

151958

Hom.:

16906

Cov.:

AF XY:

0.442

AC XY:

32844

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.681

AC:

28233

AN:

41446

American (AMR)

AF:

0.464

AC:

7080

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

1049

AN:

3468

East Asian (EAS)

AF:

0.223

AC:

1151

AN:

5172

South Asian (SAS)

AF:

0.226

AC:

1089

AN:

4818

European-Finnish (FIN)

AF:

0.352

AC:

3709

AN:

10536

Middle Eastern (MID)

AF:

0.336

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.354

AC:

24030

AN:

67940

Other (OTH)

AF:

0.416

AC:

877

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1724

3448

5172

6896

8620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

596

1192

1788

2384

2980

<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:

0.385

Hom.:

15365

Bravo

AF:

0.467

Asia WGS

AF:

0.247

AC:

858

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.75

(source)

DANN

Benign

0.64

PhyloP100

0.081

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over