7-2647239-G-A

Variant names:

• chr7-2647239-G-A
• rs1034255453
• NM_025250.3:c.391G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025250.3(TTYH3):​c.391G>A​(p.Gly131Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TTYH3 NM_025250.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.26
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025250.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTYH3	NM_025250.3	MANE Select	c.391G>A	p.Gly131Arg	missense	Exon 3 of 14	NP_079526.1	Q9C0H2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTYH3	ENST00000258796.12	TSL:1 MANE Select	c.391G>A	p.Gly131Arg	missense	Exon 3 of 14	ENSP00000258796.7	Q9C0H2-1
	TTYH3	ENST00000913086.1		c.700G>A	p.Gly234Arg	missense	Exon 4 of 15	ENSP00000583145.1
	TTYH3	ENST00000913085.1		c.391G>A	p.Gly131Arg	missense	Exon 3 of 15	ENSP00000583144.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439826 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 714762

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 41884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25636

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 38990

South Asian (SAS) AF: 0.00 AC: 0 AN: 83338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104826

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.56		Gain of MoRF binding (P = 0.0147)
MVP		0.39
MPC		0.92
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.93
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs1034255453; hg19: chr7-2686873; COSMIC: COSV105863250; COSMIC: COSV105863250;