Genetic Variant NM_002066.3:c.194G>T (chr8-142846407-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002066.3(GML):c.194G>T(p.Arg65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,562 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GML
NM_002066.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.210

Variant links:

Genes affected

GML (HGNC:4375): (glycosylphosphatidylinositol anchored molecule like) Predicted to be involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; apoptotic process; and negative regulation of cell population proliferation. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

GML links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GML	NM_002066.3 link	c.194G>T	p.Arg65Leu	missense_variant	Exon 4 of 4	ENST00000220940.2	NP_002057.1	Q99445

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GML	ENST00000220940.2 link	c.194G>T	p.Arg65Leu	missense_variant	Exon 4 of 4	1	NM_002066.3	ENSP00000220940.1		Q99445
GML	ENST00000522728.5 link	c.181+5182G>T		intron_variant	Intron 3 of 4	3		ENSP00000430799.1		E5RI31

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435562

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712616

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.017

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.57

M_CAP

Benign

0.0030

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.31

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.45

MutPred

0.50

Loss of MoRF binding (P = 0.0276);

MVP

0.31

MPC

0.73

ClinPred

0.92

GERP RS

3.5

Varity_R

0.18

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over