rs45538536

Variant names:

• chr11-2164359-G-A
• rs45538536
• NM_000360.4:c.1368C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000360.4(TH):​c.1368C>T​(p.Ser456Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,552,314 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.90
• 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: 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-2164359-G-A is Benign according to our data. Variant chr11-2164359-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304068.
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.1368C>T	p.Ser456Ser	synonymous	Exon 13 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1461C>T	p.Ser487Ser	synonymous	Exon 14 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1449C>T	p.Ser483Ser	synonymous	Exon 14 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.1368C>T	p.Ser456Ser	synonymous	Exon 13 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1461C>T	p.Ser487Ser	synonymous	Exon 14 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1449C>T	p.Ser483Ser	synonymous	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000271 AC: 56 AN: 206644 AF XY: 0.000339

Gnomad AFR exome AF: 0.0000709

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000314 AC: 440 AN: 1400112 Hom.: 2 Cov.: 31 AF XY: 0.000326 AC XY: 225 AN XY: 691174

African (AFR) AF: 0.0000652 AC: 2 AN: 30674

American (AMR) AF: 0.0000267 AC: 1 AN: 37452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23358

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36738

South Asian (SAS) AF: 0.000758 AC: 60 AN: 79152

European-Finnish (FIN) AF: 0.000295 AC: 15 AN: 50816

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5544

European-Non Finnish (NFE) AF: 0.000324 AC: 349 AN: 1078744

Other (OTH) AF: 0.000191 AC: 11 AN: 57634

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74338

African (AFR) AF: 0.0000965 AC: 4 AN: 41448

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68022

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Autosomal recessive DOPA responsive dystonia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.34
DANN	Benign	0.91
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45538536; hg19: chr11-2185589;