4-16163447-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153365.3(TAPT1):c.1565A>G(p.Asn522Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,614,008 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: TAPT1 NM_153365.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0480

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034653246).
• BP6: Variant 4-16163447-T-C is Benign according to our data. Variant chr4-16163447-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 770900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16163447-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAPT1	NM_153365.3	c.1565A>G	p.Asn522Ser	missense_variant	14/14	ENST00000405303.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAPT1	ENST00000405303.7	c.1565A>G	p.Asn522Ser	missense_variant	14/14	1	NM_153365.3	P1

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152212 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00343 AC: 854 AN: 249238 Hom.: 6 AF XY: 0.00348 AC XY: 470 AN XY: 135208

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00690

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00353 AC: 5162 AN: 1461678 Hom.: 15 Cov.: 31 AF XY: 0.00341 AC XY: 2482 AN XY: 727122

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00597

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.00364

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00312 AC: 476 AN: 152330 Hom.: 3 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74490

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00326 Hom.: 1

Bravo AF: 0.00220

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000263 AC: 1

ESP6500EA AF: 0.00290 AC: 24

ExAC AF: 0.00297 AC: 359

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TAPT1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2021	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.034
Dann	Benign	0.40
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.60	N
MutationTaster	Benign	0.63	D;D;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.071
Sift	Benign	0.42	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.068
MVP		0.082
MPC		0.25
ClinPred		0.0025	T
GERP RS		-4.6
Varity_R		0.020
gMVP		0.081

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: rs16893137; hg19: chr4-16165070; COSMIC: COSV100461227; COSMIC: COSV100461227;