17-32940899-A-C

Position:

• chr17-32940899-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000579849.6(TMEM98):​c.587A>C​(p.His196Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM98 ENST00000579849.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.73

Genes affected

TMEM98 (HGNC:24529): (transmembrane protein 98) This gene encodes a transmembrane protein. A missense mutation in this gene result in Nanophthalmos 4 (NNO4). Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 17-32940899-A-C is Pathogenic according to our data. Variant chr17-32940899-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 224331.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM98	NM_015544.3	c.587A>C	p.His196Pro	missense_variant	8/8	ENST00000579849.6	NP_056359.2
TMEM98	NM_001033504.2	c.587A>C	p.His196Pro	missense_variant	7/7		NP_001028676.1
TMEM98	NM_001301746.2	c.587A>C	p.His196Pro	missense_variant	9/9		NP_001288675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM98	ENST00000579849.6	c.587A>C	p.His196Pro	missense_variant	8/8	1	NM_015544.3	ENSP00000463245	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nanophthalmos 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.97	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.8	D;.;.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.52		Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);.;Loss of helix (P = 0.0795);
MVP		0.74
MPC		0.80
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.93

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: rs869312733; hg19: chr17-31267917;