Variant 7-2647421-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025250.3(TTYH3):c.409T>C(p.Trp137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,509,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

TTYH3
NM_025250.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.958

Variant links:

Genes affected

TTYH3 (HGNC:22222): (tweety family member 3) This gene encodes a member of the tweety family of proteins. Members of this family function as chloride anion channels. The encoded protein functions as a calcium(2+)-activated large conductance chloride(-) channel. [provided by RefSeq, Jul 2008]

TTYH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0936991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTYH3	NM_025250.3 linkuse as main transcript	c.409T>C	p.Trp137Arg	missense_variant	4/14	ENST00000258796.12	NP_079526.1	Q9C0H2-1A0A024R816Q8WYU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TTYH3	ENST00000258796.12 linkuse as main transcript	c.409T>C	p.Trp137Arg	missense_variant	4/14	1	NM_025250.3	ENSP00000258796.7	Q9C0H2-1
TTYH3	ENST00000429448.2 linkuse as main transcript	c.409T>C	p.Trp137Arg	missense_variant	4/15	2		ENSP00000413757.2	Q9C0H2-4H7C3T6
TTYH3	ENST00000407643.5 linkuse as main transcript	c.409T>C	p.Trp137Arg	missense_variant	4/13	5		ENSP00000385316.1	Q9C0H2-2

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

151754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000336

AC:

AN:

118938

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

65404

show subpopulations

Gnomad AFR exome

AF:

0.000334

Gnomad AMR exome

AF:

0.0000929

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000302

AC:

AN:

1357406

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

666880

show subpopulations

Gnomad4 AFR exome

AF:

0.000688

Gnomad4 AMR exome

AF:

0.0000926

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:

0.0000141

Gnomad4 OTH exome

AF:

0.0000355

GnomAD4 genome

AF:

0.000303

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000385

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

Jun 30, 2023

The c.409T>C (p.W137R) alteration is located in exon 4 (coding exon 4) of the TTYH3 gene. This alteration results from a T to C substitution at nucleotide position 409, causing the tryptophan (W) at amino acid position 137 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.13

Sift

Benign

0.35

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0010

B;.

Vest4

0.23

MutPred

0.55

Gain of disorder (P = 0.0016);Gain of disorder (P = 0.0016);

MVP

0.043

MPC

0.40

ClinPred

0.019

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.65

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