7-2647207-A-C

Variant names:

• chr7-2647207-A-C
• rs756015223
• NM_025250.3:c.359A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025250.3(TTYH3):​c.359A>C​(p.Tyr120Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,452,634 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y120C) has been classified as Uncertain significance.

• 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: 5.67
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.359A>C	p.Tyr120Ser	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.359A>C	p.Tyr120Ser	missense	Exon 3 of 14	ENSP00000258796.7	Q9C0H2-1
	TTYH3	ENST00000913086.1		c.668A>C	p.Tyr223Ser	missense	Exon 4 of 15	ENSP00000583145.1
	TTYH3	ENST00000913085.1		c.359A>C	p.Tyr120Ser	missense	Exon 3 of 15	ENSP00000583144.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452634 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722156

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 84958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109638

Other (OTH) AF: 0.0000167 AC: 1 AN: 60050

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.50
Sift	Benign	0.30	T
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.70		Gain of disorder (P = 0.0022)
MVP		0.26
MPC		0.73
ClinPred		0.95	D
GERP RS		5.4
PromoterAI		0.034	Neutral
Varity_R		0.84
gMVP		0.72
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756015223; hg19: chr7-2686841;