chr17-28357710-G-C

Variant names:

• chr17-28357710-G-C
• rs869025586
• NM_152464.3:c.40G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_152464.3(TMEM199):​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: TMEM199 NM_152464.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.29

Genes affected

TMEM199 (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

Verdict is Uncertain_significance. Variant got 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 id is 223000.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM199	NM_152464.3	c.40G>C	p.Ala14Pro	missense_variant	Exon 1 of 6	ENST00000292114.8	NP_689677.1
POLDIP2	NM_015584.5	c.-262C>G		upstream_gene_variant		ENST00000540200.6	NP_056399.1
POLDIP2	NM_001290145.2	c.-262C>G		upstream_gene_variant			NP_001277074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM199	ENST00000292114.8	c.40G>C	p.Ala14Pro	missense_variant	Exon 1 of 6	1	NM_152464.3	ENSP00000292114.3
POLDIP2	ENST00000540200.6	c.-262C>G		upstream_gene_variant		1	NM_015584.5	ENSP00000475924.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

TMEM199-CDG Pathogenic:1

Feb 29, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.84
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.85
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0215);
MVP		0.47
MPC		0.30
ClinPred		0.66	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs869025586; hg19: chr17-26684733;