Variant 19-54429882-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020659.4(TTYH1):c.808G>A(p.Gly270Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TTYH1
NM_020659.4 missense, splice_region

Scores

Splicing: ADA: 0.9913

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTYH1	NM_020659.4 linkuse as main transcript	c.808G>A	p.Gly270Ser	missense_variant, splice_region_variant	7/14	ENST00000376530.8	NP_065710.1	Q9H313-1
TTYH1	NM_001005367.3 linkuse as main transcript	c.808G>A	p.Gly270Ser	missense_variant, splice_region_variant	7/13		NP_001005367.1	Q9H313-3
TTYH1	NM_001201461.2 linkuse as main transcript	c.808G>A	p.Gly270Ser	missense_variant, splice_region_variant	7/14		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.808G>A	p.Gly270Ser	missense_variant, splice_region_variant	7/14	1	NM_020659.4	ENSP00000365713.3		Q9H313-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250964

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

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

Jul 30, 2023

The c.808G>A (p.G270S) alteration is located in exon 7 (coding exon 7) of the TTYH1 gene. This alteration results from a G to A substitution at nucleotide position 808, causing the glycine (G) at amino acid position 270 to be replaced by a serine (S). 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

0.16

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.30

Sift

Benign

0.056

T;T;T

Sift4G

Uncertain

0.025

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.62

MVP

0.11

MPC

1.1

ClinPred

0.99

GERP RS

4.2

Varity_R

0.34

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.070

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