rs34510659

Variant names:

• chr11-2169776-C-T
• rs34510659
• NM_000360.4:c.186G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.186G>A​(p.Ser62Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,611,736 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (157 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (161 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.12
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-2169776-C-T is Benign according to our data. Variant chr11-2169776-C-T is described in ClinVar as Benign. ClinVar VariationId is 263252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

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.186G>A	p.Ser62Ser	synonymous	Exon 2 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.279G>A	p.Ser93Ser	synonymous	Exon 3 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.267G>A	p.Ser89Ser	synonymous	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.186G>A	p.Ser62Ser	synonymous	Exon 2 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.279G>A	p.Ser93Ser	synonymous	Exon 3 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.267G>A	p.Ser89Ser	synonymous	Exon 3 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3748 AN: 152164 Hom.: 157 Cov.: 33

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.00652 AC: 1580 AN: 242176 AF XY: 0.00455

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.00502

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00264 AC: 3856 AN: 1459454 Hom.: 161 Cov.: 37 AF XY: 0.00228 AC XY: 1652 AN XY: 726006

African (AFR) AF: 0.0910 AC: 3045 AN: 33466

American (AMR) AF: 0.00584 AC: 261 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51934

Middle Eastern (MID) AF: 0.00214 AC: 12 AN: 5620

European-Non Finnish (NFE) AF: 0.0000990 AC: 110 AN: 1111550

Other (OTH) AF: 0.00661 AC: 398 AN: 60234

GnomAD4 genome AF: 0.0247 AC: 3767 AN: 152282 Hom.: 157 Cov.: 33 AF XY: 0.0233 AC XY: 1737 AN XY: 74454

African (AFR) AF: 0.0845 AC: 3512 AN: 41564

American (AMR) AF: 0.0111 AC: 170 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67988

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0126 Hom.: 34

Bravo AF: 0.0287

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.94
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs34510659; hg19: chr11-2191006;