11-2169769-C-T

Variant names:

• chr11-2169769-C-T
• rs780478399
• NM_000360.4:c.193G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000360.4(TH):​c.193G>A​(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,611,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G65G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.813
• Publications: 2 publications found

Genes affected

TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

TH Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35058603).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. 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
	TH	NM_000360.4	MANE Select	c.193G>A	p.Gly65Arg	missense	Exon 2 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.286G>A	p.Gly96Arg	missense	Exon 3 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.274G>A	p.Gly92Arg	missense	Exon 3 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.193G>A	p.Gly65Arg	missense	Exon 2 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.286G>A	p.Gly96Arg	missense	Exon 3 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.274G>A	p.Gly92Arg	missense	Exon 3 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 243524 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1459628 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 726088

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.0000448 AC: 2 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51986

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5672

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111574

Other (OTH) AF: 0.0000332 AC: 2 AN: 60252

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive DOPA responsive dystonia (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.35	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.81
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.41
Sift	Benign	0.052	T
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.29
MutPred		0.27		Gain of solvent accessibility (P = 0.0037)
MVP		0.91
MPC		0.054
ClinPred		0.17	T
GERP RS		3.5
Varity_R		0.18
gMVP		0.61
Mutation Taster		=77/23	polymorphism

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: rs780478399; hg19: chr11-2190999;