Genetic Variant SOGA3:p.Val458Met (chr6-127513004-C-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_001400265.1(MTCL3):c.1372G>A(p.Val458Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MTCL3
NM_001400265.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

SOGA3 (HGNC:21494): (MTCL family member 3) Predicted to be involved in regulation of autophagy. Predicted to be located in extracellular space. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SOGA3 links:

ENSG00000255330 (HGNC:):

ENSG00000255330 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	Protein
MTCL3	NM_001400265.1 link	c.1372G>A	p.Val458Met	missense_variant	Exon 4 of 7	NP_001387194.1
SOGA3-KIAA0408	NR_174482.1 link	n.2217G>A		non_coding_transcript_exon_variant	Exon 4 of 13
LOC107986642	XR_001744337.2 link	n.1171-1283C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
SOGA3	ENST00000525778.6 link	c.1372G>A	p.Val458Met	missense_variant	Exon 4 of 7	5	ENSP00000434570.1	Q5TF21
ENSG00000255330	ENST00000481848.6 link	n.1372G>A		non_coding_transcript_exon_variant	Exon 4 of 12	5	ENSP00000455908.1
SOGA3	ENST00000465909.3 link	c.1372G>A	p.Val458Met	missense_variant	Exon 4 of 7	5	ENSP00000435559.1	E9PJP2
SOGA3	ENST00000703793.1 link	c.823G>A	p.Val275Met	missense_variant	Exon 3 of 5		ENSP00000515479.1	A0A994J4H7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459532

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1372G>A (p.V458M) alteration is located in exon 4 (coding exon 3) of the SOGA3 gene. This alteration results from a G to A substitution at nucleotide position 1372, causing the valine (V) at amino acid position 458 to be replaced by a methionine (M). 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

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.65

MutPred

0.25

Gain of phosphorylation at T463 (P = 0.1098);Gain of phosphorylation at T463 (P = 0.1098);

MVP

0.17

ClinPred

0.96

GERP RS

5.5

Varity_R

0.37

gMVP

0.49

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over