7-2646941-G-T

Variant summary

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

The NM_025250.3(TTYH3):​c.212G>T​(p.Arg71Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,600,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TTYH3
NM_025250.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.52
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]

Genome browser will be placed here

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 rank MANE Protein UniProt
TTYH3NM_025250.3 linkc.212G>T p.Arg71Leu missense_variant Exon 2 of 14 ENST00000258796.12 NP_079526.1 Q9C0H2-1A0A024R816Q8WYU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTYH3ENST00000258796.12 linkc.212G>T p.Arg71Leu missense_variant Exon 2 of 14 1 NM_025250.3 ENSP00000258796.7 Q9C0H2-1
TTYH3ENST00000429448.2 linkc.212G>T p.Arg71Leu missense_variant Exon 2 of 15 2 ENSP00000413757.2 Q9C0H2-4H7C3T6
TTYH3ENST00000407643.5 linkc.212G>T p.Arg71Leu missense_variant Exon 2 of 13 5 ENSP00000385316.1 Q9C0H2-2
TTYH3ENST00000400376.2 linkc.233G>T p.Arg78Leu missense_variant Exon 2 of 3 4 ENSP00000383227.2 A8MXJ9

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152198
Hom.:
0
Cov.:
33
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000346
AC:
8
AN:
231122
Hom.:
0
AF XY:
0.00000790
AC XY:
1
AN XY:
126562
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:
0.0000755
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000113
AC:
164
AN:
1448428
Hom.:
0
Cov.:
45
AF XY:
0.000118
AC XY:
85
AN XY:
720728
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.000140
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74478
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000284
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.212G>T (p.R71L) alteration is located in exon 2 (coding exon 2) of the TTYH3 gene. This alteration results from a G to T substitution at nucleotide position 212, causing the arginine (R) at amino acid position 71 to be replaced by a leucine (L). 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
0.29
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;.;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.069
D
MetaRNN
Uncertain
0.44
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
M;M;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
-2.0
N;N;D
REVEL
Uncertain
0.34
Sift
Benign
0.17
T;T;D
Sift4G
Benign
0.11
T;T;D
Polyphen
1.0
D;.;.
Vest4
0.81
MVP
0.29
MPC
0.90
ClinPred
0.53
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.0
Varity_R
0.32
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs370463433; hg19: chr7-2686575; COSMIC: COSV99350180; COSMIC: COSV99350180; API