dbSNP rs3170633: GCLM:c.*3218G>A (chr1-93885772-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002061.4(GCLM):c.*3218G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 152,014 control chromosomes in the GnomAD database, including 16,897 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 0.44 ( 16897 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GCLM
NM_002061.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0870

Publications

14 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GCLM	NM_002061.4 link	c.*3218G>A	3_prime_UTR_variant	Exon 7 of 7	ENST00000370238.8	NP_002052.1	P48507-1
GCLM	NM_001308253.2 link	c.*3218G>A	3_prime_UTR_variant	Exon 6 of 6		NP_001295182.1	P48507-2
GCLM	XM_011541261.3 link	c.*3218G>A	3_prime_UTR_variant	Exon 7 of 7		XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLM	ENST00000370238.8 link	c.*3218G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_002061.4	ENSP00000359258.3		P48507-1
ENSG00000310419	ENST00000849663.1 link	n.401+3187C>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67502

AN:

151896

Hom.:

16862

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.464

Gnomad ASJ

AF:

0.302

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.415

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.445

AC:

67594

AN:

152014

Hom.:

16897

Cov.:

AF XY:

0.442

AC XY:

32833

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.681

AC:

28241

AN:

41484

American (AMR)

AF:

0.464

AC:

7083

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

1049

AN:

3470

East Asian (EAS)

AF:

0.221

AC:

1147

AN:

5180

South Asian (SAS)

AF:

0.226

AC:

1087

AN:

4820

European-Finnish (FIN)

AF:

0.351

AC:

3701

AN:

10546

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.354

AC:

24024

AN:

67930

Other (OTH)

AF:

0.416

AC:

879

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1748

3496

5243

6991

8739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.426

Hom.:

4504

Bravo

AF:

0.467

Asia WGS

AF:

0.249

AC:

864

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

1.5

(source)

DANN

Benign

0.69

PhyloP100

-0.087

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over