chr17-32940899-A-C

Variant names:

• chr17-32940899-A-C
• rs869312733
• NM_015544.3:c.587A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015544.3(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 NM_015544.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.73
• Publications: 7 publications found

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]

TMEM98 Gene-Disease associations (from GenCC):

• nanophthalmos 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 224331.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015544.3. 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
	TMEM98	NM_015544.3	MANE Select	c.587A>C	p.His196Pro	missense	Exon 8 of 8	NP_056359.2	Q9Y2Y6
	TMEM98	NM_001033504.2		c.587A>C	p.His196Pro	missense	Exon 7 of 7	NP_001028676.1	Q9Y2Y6
	TMEM98	NM_001301746.2		c.587A>C	p.His196Pro	missense	Exon 9 of 9	NP_001288675.1	Q9Y2Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM98	ENST00000579849.6	TSL:1 MANE Select	c.587A>C	p.His196Pro	missense	Exon 8 of 8	ENSP00000463245.1	Q9Y2Y6
	TMEM98	ENST00000394642.7	TSL:2	c.587A>C	p.His196Pro	missense	Exon 7 of 7	ENSP00000378138.3	Q9Y2Y6
	TMEM98	ENST00000851236.1		c.587A>C	p.His196Pro	missense	Exon 8 of 8	ENSP00000521295.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Nanophthalmos 4 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.97	L
PhyloP100		8.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.52		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
Mutation Taster		=15/85	disease causing (ClinVar)

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: rs869312733; hg19: chr17-31267917;