NM_000360.4:c.1334+127T>C

Variant names:

• chr11-2165105-A-G
• rs2070762
• NM_000360.4:c.1334+127T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.607
• Publications: 65 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.1334+127T>C		intron	N/A	NP_000351.2
	TH	NM_199292.3		c.1427+127T>C		intron	N/A	NP_954986.2
	TH	NM_199293.3		c.1415+127T>C		intron	N/A	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.1334+127T>C		intron	N/A	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.1427+127T>C		intron	N/A	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.1415+127T>C		intron	N/A	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65450 AN: 151896 Hom.: 15314 Cov.: 33

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

African (AFR) AF: 0.228 AC: 6811 AN: 29856

American (AMR) AF: 0.652 AC: 27715 AN: 42494

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11083 AN: 24226

East Asian (EAS) AF: 0.474 AC: 18172 AN: 38338

South Asian (SAS) AF: 0.504 AC: 40781 AN: 80952

European-Finnish (FIN) AF: 0.498 AC: 19870 AN: 39924

Middle Eastern (MID) AF: 0.532 AC: 2426 AN: 4556

European-Non Finnish (NFE) AF: 0.499 AC: 477892 AN: 957282

Other (OTH) AF: 0.476 AC: 25672 AN: 53908

GnomAD4 genome AF: 0.431 AC: 65494 AN: 152014 Hom.: 15328 Cov.: 33 AF XY: 0.435 AC XY: 32321 AN XY: 74300

African (AFR) AF: 0.240 AC: 9957 AN: 41476

American (AMR) AF: 0.576 AC: 8811 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1597 AN: 3464

East Asian (EAS) AF: 0.438 AC: 2248 AN: 5136

South Asian (SAS) AF: 0.504 AC: 2430 AN: 4822

European-Finnish (FIN) AF: 0.483 AC: 5108 AN: 10572

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33743 AN: 67934

Other (OTH) AF: 0.478 AC: 1011 AN: 2114

Alfa AF: 0.487 Hom.: 30673

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

Submissions by phenotype

not provided Benign:2

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)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive DOPA responsive dystonia Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.4
DANN	Benign	0.42
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070762; hg19: chr11-2186335; COSMIC: COSV51747073; COSMIC: COSV51747073;