rs372077622

Variant names:

• chr11-2169658-C-A
• rs372077622
• NM_000360.4:c.304G>T

Variant summary

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

The NM_000360.4(TH):​c.304G>T​(p.Val102Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.62
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.304G>T	p.Val102Leu	missense	Exon 2 of 13	NP_000351.2
	TH	NM_199292.3		c.397G>T	p.Val133Leu	missense	Exon 3 of 14	NP_954986.2
	TH	NM_199293.3		c.385G>T	p.Val129Leu	missense	Exon 3 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.304G>T	p.Val102Leu	missense	Exon 2 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.397G>T	p.Val133Leu	missense	Exon 3 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.385G>T	p.Val129Leu	missense	Exon 3 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248748 AF XY: 0.0000371

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000809

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461402 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727002

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52968

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

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74308

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Autosomal recessive DOPA responsive dystonia (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.47
Sift	Benign	0.51	T
Sift4G	Benign	0.43	T
Polyphen		0.031	B
Vest4		0.39
MutPred		0.40		Loss of methylation at K132 (P = 0.0388)
MVP		0.85
MPC		0.051
ClinPred		0.24	T
GERP RS		2.5
Varity_R		0.24
gMVP		0.67
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs372077622; hg19: chr11-2190888;