Genetic Variant GCLM:p.Val136Ile (chr1-93896752-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002061.4(GCLM):c.406G>A(p.Val136Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V136L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GCLM
NM_002061.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.58

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1317333).

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.406G>A	p.Val136Ile	missense	Exon 5 of 7	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.340G>A	p.Val114Ile	missense	Exon 4 of 6	NP_001295182.1	P48507-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCLM	ENST00000370238.8	TSL:1 MANE Select	c.406G>A	p.Val136Ile	missense	Exon 5 of 7	ENSP00000359258.3	P48507-1
GCLM	ENST00000615724.1	TSL:1	c.340G>A	p.Val114Ile	missense	Exon 4 of 6	ENSP00000484507.1	P48507-2
GCLM	ENST00000871361.1		c.460G>A	p.Val154Ile	missense	Exon 6 of 8	ENSP00000541420.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458636

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109050

Other (OTH)

AF:

0.00

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.0056

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

M_CAP

Benign

0.0027

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.48

PhyloP100

4.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.68

REVEL

Benign

0.11

Sift

Benign

0.20

Sift4G

Benign

0.31

Polyphen

0.0060

Vest4

0.046

MutPred

0.50

Loss of catalytic residue at V136 (P = 0.2509)

MVP

0.25

MPC

0.24

ClinPred

0.40

GERP RS

5.5

Varity_R

0.034

gMVP

0.099

Mutation Taster

=95/5

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over