7-2652219-C-G

Variant names:

• chr7-2652219-C-G
• rs754109257
• NM_025250.3:c.904C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025250.3(TTYH3):​c.904C>G​(p.Arg302Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTYH3 NM_025250.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035395533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTYH3	NM_025250.3	c.904C>G	p.Arg302Gly	missense_variant	Exon 8 of 14	ENST00000258796.12	NP_079526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTYH3	ENST00000258796.12	c.904C>G	p.Arg302Gly	missense_variant	Exon 8 of 14	1	NM_025250.3	ENSP00000258796.7
TTYH3	ENST00000429448.2	c.904C>G	p.Arg302Gly	missense_variant	Exon 8 of 15	2		ENSP00000413757.2
TTYH3	ENST00000407643.5	c.808C>G	p.Arg270Gly	missense_variant	Exon 7 of 13	5		ENSP00000385316.1
TTYH3	ENST00000403167.5	c.391C>G	p.Arg131Gly	missense_variant	Exon 4 of 10	5		ENSP00000385015.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249540 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135266

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460616 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726658

Gnomad4 AFR exome AF: 0.0000597

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.904C>G (p.R302G) alteration is located in exon 8 (coding exon 8) of the TTYH3 gene. This alteration results from a C to G substitution at nucleotide position 904, causing the arginine (R) at amino acid position 302 to be replaced by a glycine (G). 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	0.067
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.26
DEOGEN2	Benign	0.057	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.45	N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.64	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.15
MutPred		0.39		Loss of solvent accessibility (P = 0.0017);.;.;
MVP		0.043
MPC		0.29
ClinPred		0.015	T
GERP RS		0.74
Varity_R		0.24
gMVP		0.24

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

Other links and lift over

dbSNP: rs754109257; hg19: chr7-2691853;