NM_025250.3:c.359A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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 Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTYH3	NM_025250.3	c.359A>C	p.Tyr120Ser	missense_variant	Exon 3 of 14	ENST00000258796.12	NP_079526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTYH3	ENST00000258796.12	c.359A>C	p.Tyr120Ser	missense_variant	Exon 3 of 14	1	NM_025250.3	ENSP00000258796.7
TTYH3	ENST00000429448.2	c.359A>C	p.Tyr120Ser	missense_variant	Exon 3 of 15	2		ENSP00000413757.2
TTYH3	ENST00000407643.5	c.359A>C	p.Tyr120Ser	missense_variant	Exon 3 of 13	5		ENSP00000385316.1
TTYH3	ENST00000400376.2	c.*31A>C		downstream_gene_variant		4		ENSP00000383227.2

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

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.50
Sift	Benign	0.30	T;T
Sift4G	Uncertain	0.039	D;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.70		Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);
MVP		0.26
MPC		0.73
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs756015223; hg19: chr7-2686841;