Genetic Variant VMA12:p.Ala14Pro (chr17-28357710-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_152464.3(VMA12):c.40G>C(p.Ala14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

VMA12
NM_152464.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.29

Publications

2 publications found

Variant links:

Genes affected

VMA12 (HGNC:18085): (transmembrane protein 199) The protein encoded by this gene has been observed to localize to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and coat protein complex I (COPI) in some human cells. The encoded protein shares some homology with the yeast protein Vma12. Defects in this gene are a cause of congenital disorder of glycosylation, type IIp. [provided by RefSeq, Mar 2016]

VMA12 links:

ENSG00000258924 (HGNC:):

ENSG00000258924 links:

POLDIP2 (HGNC:23781): (DNA polymerase delta interacting protein 2) This gene encodes a protein that interacts with the DNA polymerase delta p50 subunit, as well as with proliferating cell nuclear antigen. The encoded protein maybe play a role in the ability of the replication fork to bypass DNA lesions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

POLDIP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-28357710-G-C is Pathogenic according to our data. Variant chr17-28357710-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 223000.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152464.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VMA12	NM_152464.3	MANE Select	c.40G>C	p.Ala14Pro	missense	Exon 1 of 6	NP_689677.1
POLDIP2	NM_015584.5	MANE Select	c.-262C>G		upstream_gene	N/A	NP_056399.1
POLDIP2	NM_001290145.2		c.-262C>G		upstream_gene	N/A	NP_001277074.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM199	ENST00000292114.8	TSL:1 MANE Select	c.40G>C	p.Ala14Pro	missense	Exon 1 of 6	ENSP00000292114.3
TMEM199	ENST00000483505.6	TSL:5	n.3G>C		non_coding_transcript_exon	Exon 1 of 5
TMEM199	ENST00000555264.6	TSL:5	n.40G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000462356.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TMEM199-CDG

Pathogenic:1

Feb 29, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.031

Eigen

Benign

0.091

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.80

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

3.3

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.68

REVEL

Benign

0.15

Sift

Benign

0.13

Sift4G

Benign

0.20

Polyphen

0.99

Vest4

0.85

MutPred

0.31

Gain of relative solvent accessibility (P = 0.0215)

MVP

0.47

MPC

0.30

ClinPred

0.66

GERP RS

4.7

PromoterAI

-0.00050

Neutral

(source)

Varity_R

0.48

gMVP

0.77

Mutation Taster

=16/84

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over