Variant 19-54415614-G-A 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_020659.4(TTYH1):c.62G>A(p.Arg21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTYH1
NM_020659.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.607

Variant links:

Genes affected

TTYH1 (HGNC:13476): (tweety family member 1) 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+)-independent, volume-sensitive large conductance chloride(-) channel. Three transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jan 2011]

TTYH1 links:

TTYH1 (HGNC:):

TTYH1 links:

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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=0.0682663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTYH1	NM_020659.4 linkuse as main transcript	c.62G>A	p.Arg21His	missense_variant	1/14	ENST00000376530.8	NP_065710.1	Q9H313-1
TTYH1	NM_001005367.3 linkuse as main transcript	c.62G>A	p.Arg21His	missense_variant	1/13		NP_001005367.1	Q9H313-3
TTYH1	NM_001201461.2 linkuse as main transcript	c.62G>A	p.Arg21His	missense_variant	1/14		NP_001188390.1	Q9H313-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTYH1	ENST00000376530.8 linkuse as main transcript	c.62G>A	p.Arg21His	missense_variant	1/14	1	NM_020659.4	ENSP00000365713.3		Q9H313-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1408378

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697758

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Apr 04, 2024

The c.62G>A (p.R21H) alteration is located in exon 1 (coding exon 1) of the TTYH1 gene. This alteration results from a G to A substitution at nucleotide position 62, causing the arginine (R) at amino acid position 21 to be replaced by a histidine (H). 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

0.25

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;.;T;T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.85

D;.;.;D;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.068

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.6

.;N;N;.;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

2.9

N;N;N;N;N

REVEL

Benign

0.074

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T

Polyphen

0.0030, 0.92, 0.011

.;B;P;.;B

Vest4

0.18, 0.16, 0.21

MutPred

0.55

.;Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);

MVP

0.27

MPC

0.45

ClinPred

0.32

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.098

gMVP

0.50

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