rs11564717

Positions:

• chr11-2165659-G-A
• chr11-2165659-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000360.4(TH):​c.1200+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,612,402 control chromosomes in the GnomAD database, including 208 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 0.010 (7 hom., cov: 32)
  • Exomes 𝑓: 0.015 (201 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.512

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-2165659-G-A is Benign according to our data. Variant chr11-2165659-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263251.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=5}. Variant chr11-2165659-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1542/152212) while in subpopulation NFE AF= 0.0176 (1199/67974). AF 95% confidence interval is 0.0168. There are 7 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1200+9C>T		intron_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1293+9C>T		intron_variant			NP_954986.2
TH	NM_199293.3	c.1281+9C>T		intron_variant			NP_954987.2
TH	XM_011520335.3	c.1212+9C>T		intron_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1200+9C>T		intron_variant		1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1542 AN: 152094 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00966 AC: 2403 AN: 248780 Hom.: 22 AF XY: 0.00990 AC XY: 1337 AN XY: 135092

Gnomad AFR exome AF: 0.00256

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0146 AC: 21255 AN: 1460190 Hom.: 201 Cov.: 32 AF XY: 0.0143 AC XY: 10418 AN XY: 726402

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00383

Gnomad4 ASJ exome AF: 0.00785

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.00539

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0101 AC: 1542 AN: 152212 Hom.: 7 Cov.: 32 AF XY: 0.00917 AC XY: 682 AN XY: 74406

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0130 Hom.: 9

Bravo AF: 0.00991

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2016	- -
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	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. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Generalized dystonia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

TH gene mutations are associated with dystonias. However, more studies are required to ascertain the role of this particular variant (rs11564717) in triggering dystonia. -

Transient Neonatal Diabetes, Dominant/Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.45

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: rs11564717; hg19: chr11-2186889;