Genetic Variant TUFT1:p.Gly146Asp (chr1-151566185-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020127.3(TUFT1):c.437G>A(p.Gly146Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000356 in 1,611,206 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

TUFT1
NM_020127.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.20

Variant links:

Genes affected

TUFT1 (HGNC:12422): (tuftelin 1) Tuftelin is an acidic protein that is thought to play a role in dental enamel mineralization and is implicated in caries susceptibility. It is also thought to be involved with adaptation to hypoxia, mesenchymal stem cell function, and neurotrophin nerve growth factor mediated neuronal differentiation. [provided by RefSeq, Aug 2014]

TUFT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TUFT1	NM_020127.3 link	c.437G>A	p.Gly146Asp	missense_variant	Exon 6 of 13	ENST00000368849.8	NP_064512.1	Q9NNX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUFT1	ENST00000368849.8 link	c.437G>A	p.Gly146Asp	missense_variant	Exon 6 of 13	1	NM_020127.3	ENSP00000357842.3		Q9NNX1-1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000149

AC:

AN:

248368

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

134158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000320

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000371

AC:

541

AN:

1459112

Hom.:

Cov.:

AF XY:

0.000354

AC XY:

257

AN XY:

725636

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.000459

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000210

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000298

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.437G>A (p.G146D) alteration is located in exon 6 (coding exon 6) of the TUFT1 gene. This alteration results from a G to A substitution at nucleotide position 437, causing the glycine (G) at amino acid position 146 to be replaced by an aspartic acid (D). 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

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

T;T;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;N;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.099

T;D;T;.

Sift4G

Benign

0.16

T;T;T;D

Polyphen

1.0

D;.;D;.

Vest4

0.78

MVP

0.67

MPC

0.74

ClinPred

0.46

GERP RS

4.1

Varity_R

0.13

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over