rs200462975

Positions:

• chr11-2168699-GAGAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000360.4(TH):​c.313-38_313-35del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 968,646 control chromosomes in the GnomAD database, including 362 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (41 hom., cov: 30)
  • Exomes 𝑓: 0.0089 (321 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0720

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 11-2168699-GAGAA-G is Benign according to our data. Variant chr11-2168699-GAGAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 263255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.313-38_313-35del		intron_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.406-38_406-35del		intron_variant			NP_954986.2
TH	NM_199293.3	c.394-38_394-35del		intron_variant			NP_954987.2
TH	XM_011520335.3	c.325-38_325-35del		intron_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.313-38_313-35del		intron_variant		1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1383 AN: 133082 Hom.: 41 Cov.: 30

Gnomad AFR AF: 0.00320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.0118

GnomAD3 exomes AF: 0.0220 AC: 4504 AN: 204318 Hom.: 250 AF XY: 0.0173 AC XY: 1946 AN XY: 112634

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.000441

Gnomad EAS exome AF: 0.0137

Gnomad SAS exome AF: 0.000473

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.00893 AC: 7464 AN: 835474 Hom.: 321 AF XY: 0.00776 AC XY: 3314 AN XY: 426974

Gnomad4 AFR exome AF: 0.00214

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.000332

Gnomad4 EAS exome AF: 0.0416

Gnomad4 SAS exome AF: 0.000681

Gnomad4 FIN exome AF: 0.0487

Gnomad4 NFE exome AF: 0.000817

Gnomad4 OTH exome AF: 0.00936

GnomAD4 genome AF: 0.0104 AC: 1387 AN: 133172 Hom.: 41 Cov.: 30 AF XY: 0.0126 AC XY: 797 AN XY: 63152

Gnomad4 AFR AF: 0.00319

Gnomad4 AMR AF: 0.0591

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0512

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.0116

Alfa AF: 0.00648 Hom.: 5

Bravo AF: 0.0126

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs200462975; hg19: chr11-2189929;