Variant 10-25023657-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024838.5(THNSL1):c.434T>C(p.Leu145Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

THNSL1
NM_024838.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

THNSL1 (HGNC:26160): (threonine synthase like 1)

THNSL1 links:

ENKUR (HGNC:28388): (enkurin, TRPC channel interacting protein) This gene encodes a protein that interacts with calmodulin and several transient receptor potential canonical cation channel proteins. The encoded protein may function as an adaptor to localize signal transduction machinery to calcium channels. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ENKUR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THNSL1	NM_024838.5 linkuse as main transcript	c.434T>C	p.Leu145Pro	missense_variant	3/3	ENST00000376356.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
THNSL1	ENST00000376356.5 linkuse as main transcript	c.434T>C	p.Leu145Pro	missense_variant	3/3	1	NM_024838.5	P1
ENKUR	ENST00000615958.4 linkuse as main transcript	c.38-27788A>G		intron_variant		1
THNSL1	ENST00000524413.5 linkuse as main transcript	c.434T>C	p.Leu145Pro	missense_variant	3/3	3		P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251222

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135784

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.434T>C (p.L145P) alteration is located in exon 3 (coding exon 1) of the THNSL1 gene. This alteration results from a T to C substitution at nucleotide position 434, causing the leucine (L) at amino acid position 145 to be replaced by a proline (P). 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

0.91

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.87

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

D;D

Vest4

0.68

MutPred

0.83

Gain of disorder (P = 0.0163);Gain of disorder (P = 0.0163);

MVP

0.62

MPC

0.24

ClinPred

0.91

GERP RS

5.7

Varity_R

0.96

gMVP

0.88

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