rs3842726

Variant names:

• chr11-2163897-C-G
• rs3842726
• ENST00000729705.1:n.175-3914C>G

Variant summary

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

The ENST00000729705.1(ENSG00000295384):​n.175-3914C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 209,268 control chromosomes in the GnomAD database, including 1,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1505 hom., cov: 33)
  • Exomes 𝑓: 0.014 (101 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.459
• Publications: 3 publications found

Genes affected

ENSG00000295384 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-2163897-C-G is Benign according to our data. Variant chr11-2163897-C-G is described in ClinVar as Benign. ClinVar VariationId is 1274135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000729705.1. 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.*336G>C		downstream_gene	N/A	NP_000351.2
	TH	NM_199292.3		c.*336G>C		downstream_gene	N/A	NP_954986.2
	TH	NM_199293.3		c.*336G>C		downstream_gene	N/A	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000295384	ENST00000729705.1		n.175-3914C>G		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.226-3914C>G		intron	N/A
	TH	ENST00000352909.8	TSL:1 MANE Select	c.*336G>C		downstream_gene	N/A	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11841 AN: 152090 Hom.: 1494 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.0549

GnomAD4 exome AF: 0.0137 AC: 779 AN: 57060 Hom.: 101 Cov.: 0 AF XY: 0.0122 AC XY: 351 AN XY: 28656

African (AFR) AF: 0.269 AC: 576 AN: 2140

American (AMR) AF: 0.0232 AC: 36 AN: 1552

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 12 AN: 2446

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00 AC: 0 AN: 550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3424

Middle Eastern (MID) AF: 0.0222 AC: 7 AN: 316

European-Non Finnish (NFE) AF: 0.00120 AC: 45 AN: 37514

Other (OTH) AF: 0.0246 AC: 103 AN: 4184

GnomAD4 genome AF: 0.0780 AC: 11873 AN: 152208 Hom.: 1505 Cov.: 33 AF XY: 0.0751 AC XY: 5589 AN XY: 74424

African (AFR) AF: 0.267 AC: 11088 AN: 41494

American (AMR) AF: 0.0348 AC: 533 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 67996

Other (OTH) AF: 0.0543 AC: 115 AN: 2116

Alfa AF: 0.0610 Hom.: 126

Bravo AF: 0.0900

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 15, 2021

GeneDx

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	-0.90
CADD	Benign	2.0
DANN	Benign	0.49
PhyloP100		-0.46

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3842726; hg19: chr11-2185127;