17-28357690-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PS1_Moderate PM2 BP4_Strong

The NM_152464.3(TMEM199):​c.20C>G​(p.Ala7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM199 NM_152464.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326

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 0 ACMG points.

• PS1: Transcript NM_152464.3 (TMEM199) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05862707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM199	NM_152464.3	c.20C>G	p.Ala7Gly	missense_variant	Exon 1 of 6	ENST00000292114.8	NP_689677.1
POLDIP2	NM_015584.5	c.-242G>C		upstream_gene_variant		ENST00000540200.6	NP_056399.1
POLDIP2	NM_001290145.2	c.-242G>C		upstream_gene_variant			NP_001277074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM199	ENST00000292114.8	c.20C>G	p.Ala7Gly	missense_variant	Exon 1 of 6	1	NM_152464.3	ENSP00000292114.3
POLDIP2	ENST00000540200.6	c.-242G>C		upstream_gene_variant		1	NM_015584.5	ENSP00000475924.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247246 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460336 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.66
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.049
Sift	Benign	0.17	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.23		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.10
MPC		0.23
ClinPred		0.52	D
GERP RS		1.7
Varity_R		0.055
gMVP		0.45

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: rs369488804; hg19: chr17-26684713;