4-16163513-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153365.3(TAPT1):c.1499C>T(p.Ser500Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000608 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: TAPT1 NM_153365.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.46

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039425284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAPT1	NM_153365.3	c.1499C>T	p.Ser500Phe	missense_variant	14/14	ENST00000405303.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAPT1	ENST00000405303.7	c.1499C>T	p.Ser500Phe	missense_variant	14/14	1	NM_153365.3	P1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000478 AC: 119 AN: 248970 Hom.: 0 AF XY: 0.000526 AC XY: 71 AN XY: 135078

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000634 AC: 927 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.000613 AC XY: 446 AN XY: 727044

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000777

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74474

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000739 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000513 AC: 62

EpiCase AF: 0.00109

EpiControl AF: 0.00125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.1499C>T (p.S500F) alteration is located in exon 14 (coding exon 14) of the TAPT1 gene. This alteration results from a C to T substitution at nucleotide position 1499, causing the serine (S) at amino acid position 500 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 500 of the TAPT1 protein (p.Ser500Phe). This variant is present in population databases (rs200723168, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TAPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1522735). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.10
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.64	P
Vest4		0.38
MVP		0.093
MPC		0.58
ClinPred		0.049	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs200723168; hg19: chr4-16165136;