NM_025250.3:c.212G>A

Variant names:

• chr7-2646941-G-A
• rs370463433
• NM_025250.3:c.212G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025250.3(TTYH3):​c.212G>A​(p.Arg71Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R71G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TTYH3 NM_025250.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTYH3	NM_025250.3	c.212G>A	p.Arg71Gln	missense_variant	Exon 2 of 14	ENST00000258796.12	NP_079526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTYH3	ENST00000258796.12	c.212G>A	p.Arg71Gln	missense_variant	Exon 2 of 14	1	NM_025250.3	ENSP00000258796.7
TTYH3	ENST00000429448.2	c.212G>A	p.Arg71Gln	missense_variant	Exon 2 of 15	2		ENSP00000413757.2
TTYH3	ENST00000407643.5	c.212G>A	p.Arg71Gln	missense_variant	Exon 2 of 13	5		ENSP00000385316.1
TTYH3	ENST00000400376.2	c.233G>A	p.Arg78Gln	missense_variant	Exon 2 of 3	4		ENSP00000383227.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000865 AC: 2 AN: 231122 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126562

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: 0.00000944

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448430 Hom.: 0 Cov.: 45 AF XY: 0.00000277 AC XY: 2 AN XY: 720728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000451

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.071	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.77
MutPred		0.49		Gain of ubiquitination at K74 (P = 0.0716);Gain of ubiquitination at K74 (P = 0.0716);.;
MVP		0.20
MPC		0.89
ClinPred		0.82	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.30
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370463433; hg19: chr7-2686575;