1-93909115-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002061.4(GCLM):c.49A>T(p.Thr17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,438,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GCLM
NM_002061.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17806295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLM	NM_002061.4 link	c.49A>T	p.Thr17Ser	missense_variant	Exon 1 of 7	ENST00000370238.8	NP_002052.1	P48507-1
GCLM	NM_001308253.2 link	c.49A>T	p.Thr17Ser	missense_variant	Exon 1 of 6		NP_001295182.1	P48507-2
GCLM	XM_047418031.1 link	c.49A>T	p.Thr17Ser	missense_variant	Exon 1 of 7		XP_047273987.1
GCLM	XM_011541261.3 link	c.-589A>T		upstream_gene_variant			XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GCLM	ENST00000370238.8 link	c.49A>T	p.Thr17Ser	missense_variant	Exon 1 of 7	1	NM_002061.4	ENSP00000359258.3	P48507-1
GCLM	ENST00000615724.1 link	c.49A>T	p.Thr17Ser	missense_variant	Exon 1 of 6	1		ENSP00000484507.1	P48507-2
GCLM	ENST00000462183.1 link	n.-191A>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

76628

Hom.:

AF XY:

0.00

AC XY:

AN XY:

44146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000718

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1286140

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

634502

show subpopulations

Gnomad4 AFR exome

AF:

0.000644

Gnomad4 AMR exome

AF:

0.0000813

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.74e-7

Gnomad4 OTH exome

AF:

0.0000572

GnomAD4 genome

AF:

0.000178

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.000627

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.0000363

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49A>T (p.T17S) alteration is located in exon 1 (coding exon 1) of the GCLM gene. This alteration results from a A to T substitution at nucleotide position 49, causing the threonine (T) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.68

T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.55

N;.

REVEL

Benign

0.081

Sift

Benign

0.16

T;.

Sift4G

Benign

0.23

T;T

Polyphen

0.055

B;.

Vest4

0.14

MutPred

0.36

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);

MVP

0.37

MPC

1.9

ClinPred

0.41

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over