Genetic Variant TH:c.1334+127T>C (chr11-2165105-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000360.4(TH):c.1334+127T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,423,550 control chromosomes in the GnomAD database, including 174,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 15328 hom., cov: 33)

Exomes 𝑓: 0.50 ( 158957 hom. )

Consequence

TH
NM_000360.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.607

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 11-2165105-A-G is Benign according to our data. Variant chr11-2165105-A-G is described in ClinVar as [Benign]. Clinvar id is 1164243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.1334+127T>C	intron_variant	Intron 12 of 12	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 link	c.1427+127T>C	intron_variant	Intron 13 of 13		NP_954986.2	P07101-1P78428
TH	NM_199293.3 link	c.1415+127T>C	intron_variant	Intron 13 of 13		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 link	c.1346+127T>C	intron_variant	Intron 12 of 12		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 link	c.1334+127T>C		intron_variant	Intron 12 of 12	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.431

AC:

65450

AN:

151896

Hom.:

15314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.240

Gnomad AMI

AF:

0.493

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.504

Gnomad FIN

AF:

0.483

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.474

GnomAD4 exome

AF:

0.496

AC:

630422

AN:

1271536

Hom.:

158957

AF XY:

0.496

AC XY:

316625

AN XY:

638710

show subpopulations

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.652

Gnomad4 ASJ exome

AF:

0.457

Gnomad4 EAS exome

AF:

0.474

Gnomad4 SAS exome

AF:

0.504

Gnomad4 FIN exome

AF:

0.498

Gnomad4 NFE exome

AF:

0.499

Gnomad4 OTH exome

AF:

0.476

GnomAD4 genome

AF:

0.431

AC:

65494

AN:

152014

Hom.:

15328

Cov.:

AF XY:

0.435

AC XY:

32321

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.240

Gnomad4 AMR

AF:

0.576

Gnomad4 ASJ

AF:

0.461

Gnomad4 EAS

AF:

0.438

Gnomad4 SAS

AF:

0.504

Gnomad4 FIN

AF:

0.483

Gnomad4 NFE

AF:

0.497

Gnomad4 OTH

AF:

0.478

Alfa

AF:

0.487

Hom.:

23097

Bravo

AF:

0.427

Asia WGS

AF:

0.468

AC:

1626

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18208403) -

Autosomal recessive DOPA responsive dystonia

Benign:2

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

9.4

DANN

Benign

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over