rs76719766

Variant names:

• chr11-2166713-G-A
• rs76719766
• NM_000360.4:c.897C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_199292.3(TH):​c.990C>T​(p.Phe330Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,552,354 control chromosomes in the GnomAD database, including 1 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 0.00058 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: TH NM_199292.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.378
• 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-2166713-G-A is Benign according to our data. Variant chr11-2166713-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304074.
• BP7: Synonymous conserved (PhyloP=0.378 with no splicing effect.

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.897C>T	p.Phe299Phe	synonymous	Exon 8 of 13	NP_000351.2
	TH	NM_199292.3		c.990C>T	p.Phe330Phe	synonymous	Exon 9 of 14	NP_954986.2
	TH	NM_199293.3		c.978C>T	p.Phe326Phe	synonymous	Exon 9 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.897C>T	p.Phe299Phe	synonymous	Exon 8 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.990C>T	p.Phe330Phe	synonymous	Exon 9 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.978C>T	p.Phe326Phe	synonymous	Exon 9 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152192 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000424 AC: 62 AN: 146332 AF XY: 0.000531

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000848

Gnomad OTH exome AF: 0.000709

GnomAD4 exome AF: 0.00104 AC: 1460 AN: 1400046 Hom.: 0 Cov.: 64 AF XY: 0.000990 AC XY: 684 AN XY: 690806

African (AFR) AF: 0.000220 AC: 7 AN: 31876

American (AMR) AF: 0.000502 AC: 18 AN: 35862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 36060

South Asian (SAS) AF: 0.000189 AC: 15 AN: 79450

European-Finnish (FIN) AF: 0.0000418 AC: 2 AN: 47824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00126 AC: 1356 AN: 1080056

Other (OTH) AF: 0.00107 AC: 62 AN: 58076

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152308 Hom.: 1 Cov.: 34 AF XY: 0.000577 AC XY: 43 AN XY: 74474

African (AFR) AF: 0.000192 AC: 8 AN: 41560

American (AMR) AF: 0.000849 AC: 13 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000559 Hom.: 0

Bravo AF: 0.000574

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		0.38
Mutation Taster		=99/1	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: rs76719766; hg19: chr11-2187943;