rs869312980

chr4-16176168-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_153365.3(TAPT1):c.1058A>T(p.Asp353Val) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D353N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TAPT1 NM_153365.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.64

Genes affected

TAPT1 (HGNC:26887): (transmembrane anterior posterior transformation 1) This gene encodes a highly conserved protein that localizes to the centrosome and/or ciliary basal body. Mutations in this gene disrupt Golgi morphology and trafficking and normal primary cilium formation and these mutations are congenitally manifested by severe undermineralization of the intra-uterine skeleton. A mutation in the mouse ortholog of this gene results in homeotic, posterior-to-anterior transformations of the axial skeleton which are similar to the phenotype of mouse homeobox C8 gene mutants. In mouse, this gene is thought to function downstream of homeobox C8 to transduce extracellular patterning information during axial skeleton development. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 4-16176168-T-A is Pathogenic according to our data. Variant chr4-16176168-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 224907.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAPT1	NM_153365.3	c.1058A>T	p.Asp353Val	missense_variant	9/14	ENST00000405303.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAPT1	ENST00000405303.7	c.1058A>T	p.Asp353Val	missense_variant	9/14	1	NM_153365.3	P1
TAPT1	ENST00000488714.2	n.374A>T		non_coding_transcript_exon_variant	2/2	3
TAPT1	ENST00000513782.1	c.437A>T	p.Asp146Val	missense_variant, NMD_transcript_variant	5/9	2
TAPT1	ENST00000505603.5	c.*573A>T		3_prime_UTR_variant, NMD_transcript_variant	8/13	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Complex lethal osteochondrodysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.87		Gain of catalytic residue at D353 (P = 0.0352);
MVP		0.81
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs869312980; hg19: chr4-16177791;