17-28357690-C-T

Variant names:

• chr17-28357690-C-T
• rs369488804
• NM_152464.3:c.20C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS1

The NM_152464.3(VMA12):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: VMA12 NM_152464.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.326
• Publications: 3 publications found

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]

ENSG00000258924 (HGNC:):

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-28357690-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 218965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.020415306).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000205 (30/1460336) while in subpopulation AMR AF = 0.00038 (17/44718). AF 95% confidence interval is 0.000242. There are 0 homozygotes in GnomAdExome4. There are 15 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA12	NM_152464.3	MANE Select	c.20C>T	p.Ala7Val	missense	Exon 1 of 6	NP_689677.1	Q8N511
	POLDIP2	NM_015584.5	MANE Select	c.-242G>A		upstream_gene	N/A	NP_056399.1	Q9Y2S7
	POLDIP2	NM_001290145.2		c.-242G>A		upstream_gene	N/A	NP_001277074.1	B4DEM9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA12	ENST00000292114.8	TSL:1 MANE Select	c.20C>T	p.Ala7Val	missense	Exon 1 of 6	ENSP00000292114.3	Q8N511
	VMA12	ENST00000971958.1		c.20C>T	p.Ala7Val	missense	Exon 1 of 6	ENSP00000642017.1
	VMA12	ENST00000555264.6	TSL:5	n.20C>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000462356.1	J3KS81

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000890 AC: 22 AN: 247246 AF XY: 0.0000819

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460336 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 726506

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.000380 AC: 17 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111870

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.8
DANN	Benign	0.91
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.18	N
PhyloP100		0.33
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.072
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.18
MVP		0.030
MPC		0.22
ClinPred		0.028	T
GERP RS		1.7
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.22

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

Other links and lift over

dbSNP: rs369488804; hg19: chr17-26684713;