chr17-32940889-G-C

Variant names:

• chr17-32940889-G-C
• rs587777690
• NM_015544.3:c.577G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_015544.3(TMEM98):​c.577G>C​(p.Ala193Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM98 NM_015544.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.36
• Publications: 10 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 Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-32940889-G-C is Pathogenic according to our data. Variant chr17-32940889-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 155721.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM98	NM_015544.3	MANE Select	c.577G>C	p.Ala193Pro	missense	Exon 8 of 8	NP_056359.2
	TMEM98	NM_001033504.2		c.577G>C	p.Ala193Pro	missense	Exon 7 of 7	NP_001028676.1
	TMEM98	NM_001301746.2		c.577G>C	p.Ala193Pro	missense	Exon 9 of 9	NP_001288675.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM98	ENST00000579849.6	TSL:1 MANE Select	c.577G>C	p.Ala193Pro	missense	Exon 8 of 8	ENSP00000463245.1
	TMEM98	ENST00000394642.7	TSL:2	c.577G>C	p.Ala193Pro	missense	Exon 7 of 7	ENSP00000378138.3
	TMEM98	ENST00000439138.5	TSL:3	c.577G>C	p.Ala193Pro	missense	Exon 9 of 9	ENSP00000406394.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nanophthalmos 4 Pathogenic:1

Aug 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		9.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.73
Sift	Benign	0.042	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.88
MutPred		0.40		Loss of helix (P = 0.0104)
MVP		0.67
MPC		1.1
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.68
gMVP		0.89
Mutation Taster		=10/90	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: rs587777690; hg19: chr17-31267907;