Genetic Variant VMA12:p.Arg31Leu (chr17-28357762-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_152464.3(VMA12):c.92G>T(p.Arg31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,204 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VMA12
NM_152464.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.66

Publications

0 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-28357762-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA12	NM_152464.3 link	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 6	ENST00000292114.8	NP_689677.1	Q8N511
POLDIP2	NM_015584.5 link	c.-314C>A		upstream_gene_variant		ENST00000540200.6	NP_056399.1	Q9Y2S7
POLDIP2	NM_001290145.2 link	c.-314C>A		upstream_gene_variant			NP_001277074.1	Q9Y2S7B4DEM9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM199	ENST00000292114.8 link	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 6	1	NM_152464.3	ENSP00000292114.3		Q8N511
POLDIP2	ENST00000540200.6 link	c.-314C>A		upstream_gene_variant		1	NM_015584.5	ENSP00000475924.2		Q9Y2S7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0095

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

3.7

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.81

REVEL

Benign

0.11

Sift

Uncertain

0.018

Sift4G

Uncertain

0.011

Polyphen

0.84

Vest4

0.64

MutPred

0.40

Loss of MoRF binding (P = 0.0183);

MVP

0.26

MPC

0.65

ClinPred

0.60

GERP RS

2.9

PromoterAI

-0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.16

gMVP

0.64

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