17-32939499-A-C

Position:

• chr17-32939499-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000579849.6(TMEM98):​c.436A>C​(p.Met146Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM98 ENST00000579849.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.85

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM98	NM_015544.3	c.436A>C	p.Met146Leu	missense_variant	7/8	ENST00000579849.6	NP_056359.2
TMEM98	NM_001033504.2	c.436A>C	p.Met146Leu	missense_variant	6/7		NP_001028676.1
TMEM98	NM_001301746.2	c.436A>C	p.Met146Leu	missense_variant	8/9		NP_001288675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM98	ENST00000579849.6	c.436A>C	p.Met146Leu	missense_variant	7/8	1	NM_015544.3	ENSP00000463245	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2024

The c.436A>C (p.M146L) alteration is located in exon 7 (coding exon 5) of the TMEM98 gene. This alteration results from a A to C substitution at nucleotide position 436, causing the methionine (M) at amino acid position 146 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.94	N;.;N
REVEL	Benign	0.26
Sift	Benign	0.29	T;.;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.30	B;B;.
Vest4		0.80
MutPred		0.28		Loss of catalytic residue at V142 (P = 0.0474);Loss of catalytic residue at V142 (P = 0.0474);Loss of catalytic residue at V142 (P = 0.0474);
MVP		0.21
MPC		0.36
ClinPred		0.66	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-31266517;