Genetic Variant THNSL1:p.Gln176Pro (chr10-25023750-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024838.5(THNSL1):c.527A>C(p.Gln176Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q176R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THNSL1
NM_024838.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.88

Publications

0 publications found

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:

ENSG00000285859 (HGNC:):

ENSG00000285859 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16891146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THNSL1	NM_024838.5 link	c.527A>C	p.Gln176Pro	missense_variant	Exon 3 of 3	ENST00000376356.5	NP_079114.3	Q8IYQ7Q9H6P9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THNSL1	ENST00000376356.5 link	c.527A>C	p.Gln176Pro	missense_variant	Exon 3 of 3	1	NM_024838.5	ENSP00000365534.4	Q8IYQ7
ENKUR	ENST00000615958.4 link	c.38-27881T>G		intron_variant	Intron 2 of 5	1		ENSP00000478989.1	A0A087WUX1
THNSL1	ENST00000524413.5 link	c.527A>C	p.Gln176Pro	missense_variant	Exon 3 of 3	3		ENSP00000434887.1	Q8IYQ7
ENSG00000285859	ENST00000648191.1 link	n.336+1842A>C		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727108

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0052

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L

PhyloP100

2.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.084

Sift

Benign

0.069

T;T

Sift4G

Benign

0.094

T;T

Polyphen

0.0090

B;B

Vest4

0.23

MutPred

0.66

Loss of MoRF binding (P = 0.0445);Loss of MoRF binding (P = 0.0445);

MVP

0.38

MPC

0.031

ClinPred

0.17

GERP RS

0.25

Varity_R

0.51

gMVP

0.72

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over