11-2165311-C-G

Variant names:

• chr11-2165311-C-G
• rs184106392
• NM_000360.4:c.1255G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000360.4(TH):​c.1255G>C​(p.Val419Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,362 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. V419M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.650
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.1255G>C	p.Val419Leu	missense	Exon 12 of 13	NP_000351.2
	TH	NM_199292.3		c.1348G>C	p.Val450Leu	missense	Exon 13 of 14	NP_954986.2
	TH	NM_199293.3		c.1336G>C	p.Val446Leu	missense	Exon 13 of 14	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.1255G>C	p.Val419Leu	missense	Exon 12 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.1348G>C	p.Val450Leu	missense	Exon 13 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.1336G>C	p.Val446Leu	missense	Exon 13 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460362 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726478

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.65
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.39
Sift	Benign	0.21	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.26
MutPred		0.48		Gain of helix (P = 0.132)
MVP		0.77
MPC		0.58
ClinPred		0.30	T
GERP RS		1.7
Varity_R		0.38
gMVP		0.57
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs184106392; hg19: chr11-2186541;