7-2647197-A-T

Variant names:

• chr7-2647197-A-T
• NM_025250.3:c.349A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025250.3(TTYH3):​c.349A>T​(p.Arg117Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,312 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: 2.24

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTYH3	NM_025250.3	c.349A>T	p.Arg117Trp	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.349A>T	p.Arg117Trp	missense_variant	Exon 3 of 14	1	NM_025250.3	ENSP00000258796.7
TTYH3	ENST00000429448.2	c.349A>T	p.Arg117Trp	missense_variant	Exon 3 of 15	2		ENSP00000413757.2
TTYH3	ENST00000407643.5	c.349A>T	p.Arg117Trp	missense_variant	Exon 3 of 13	5		ENSP00000385316.1
TTYH3	ENST00000400376.2	c.*21A>T		downstream_gene_variant		4		ENSP00000383227.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454312 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723050

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.47	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.77		Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);
MVP		0.15
MPC		0.86
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-2686831;