rs11564716

Positions:

• chr11-2167446-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000360.4(TH):​c.684G>A​(p.Glu228Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,563,192 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (66 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.856

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-2167446-C-T is Benign according to our data. Variant chr11-2167446-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 242255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2167446-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.856 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00681 (1038/152334) while in subpopulation NFE AF= 0.00969 (659/68032). AF 95% confidence interval is 0.00907. There are 12 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.684G>A	p.Glu228Glu	synonymous_variant	6/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.777G>A	p.Glu259Glu	synonymous_variant	7/14		NP_954986.2
TH	NM_199293.3	c.765G>A	p.Glu255Glu	synonymous_variant	7/14		NP_954987.2
TH	XM_011520335.3	c.696G>A	p.Glu232Glu	synonymous_variant	6/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.684G>A	p.Glu228Glu	synonymous_variant	6/13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1038 AN: 152216 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00809

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00559 AC: 970 AN: 173630 Hom.: 6 AF XY: 0.00524 AC XY: 484 AN XY: 92338

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00393

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000505

Gnomad FIN exome AF: 0.00929

Gnomad NFE exome AF: 0.00918

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00882 AC: 12440 AN: 1410858 Hom.: 66 Cov.: 33 AF XY: 0.00855 AC XY: 5961 AN XY: 696986

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.00412

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000612

Gnomad4 FIN exome AF: 0.00852

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00724

GnomAD4 genome AF: 0.00681 AC: 1038 AN: 152334 Hom.: 12 Cov.: 33 AF XY: 0.00655 AC XY: 488 AN XY: 74480

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00809

Gnomad4 NFE AF: 0.00969

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00712 Hom.: 4

Bravo AF: 0.00655

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TH: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.8
DANN	Benign	0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs11564716; hg19: chr11-2188676;