rs11564716

Variant names:

• chr11-2167446-C-G
• rs11564716
• NM_000360.4:c.684G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-2167446-C-G
• chr11-2167446-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_199292.3(TH):​c.777G>C​(p.Glu259Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,868 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. Synonymous variant affecting the same amino acid position (i.e. E259E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TH NM_199292.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.856
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• tyrosine hydroxylase deficiency

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

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199292.3. 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
	TH	NM_000360.4	MANE Select	c.684G>C	p.Glu228Asp	missense	Exon 6 of 13	NP_000351.2
	TH	NM_199292.3		c.777G>C	p.Glu259Asp	missense	Exon 7 of 14	NP_954986.2
	TH	NM_199293.3		c.765G>C	p.Glu255Asp	missense	Exon 7 of 14	NP_954987.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.684G>C	p.Glu228Asp	missense	Exon 6 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.777G>C	p.Glu259Asp	missense	Exon 7 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.765G>C	p.Glu255Asp	missense	Exon 7 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410868 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 696992

African (AFR) AF: 0.00 AC: 0 AN: 32454

American (AMR) AF: 0.00 AC: 0 AN: 37386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 37222

South Asian (SAS) AF: 0.00 AC: 0 AN: 80108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085682

Other (OTH) AF: 0.00 AC: 0 AN: 58456

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.86
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.020	D
Polyphen		0.14	B
Vest4		0.80
MutPred		0.86		Loss of ubiquitination at K264 (P = 0.063)
MVP		0.98
MPC		0.28
ClinPred		0.97	D
GERP RS		0.23
Varity_R		0.77
gMVP		0.87
Mutation Taster		=28/72	disease causing

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: rs11564716; hg19: chr11-2188676;