18-24118138-G-A

Position:

• chr18-24118138-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001135993.2(TTC39C):​c.1092G>A​(p.Met364Ile) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC39C NM_001135993.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

TTC39C (HGNC:26595): (tetratricopeptide repeat domain 39C) Predicted to be involved in cilium assembly and otolith morphogenesis. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000264924 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC39C	NM_001135993.2	c.1092G>A	p.Met364Ile	missense_variant	8/14	ENST00000317571.8	NP_001129465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC39C	ENST00000317571.8	c.1092G>A	p.Met364Ile	missense_variant	8/14	1	NM_001135993.2	ENSP00000323645.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.1092G>A (p.M364I) alteration is located in exon 8 (coding exon 8) of the TTC39C gene. This alteration results from a G to A substitution at nucleotide position 1092, causing the methionine (M) at amino acid position 364 to be replaced by an isoleucine (I). 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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;T;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.74	N;N;N;.
REVEL	Benign	0.27
Sift	Benign	0.18	T;T;T;.
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.85	.;P;.;.
Vest4		0.78
MutPred		0.64		.;Loss of catalytic residue at M364 (P = 0.0065);.;.;
MVP		0.73
MPC		0.90
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.28
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr18-21698102;