chr11-2166492-C-A

Variant names:

• chr11-2166492-C-A
• rs11826260
• NM_000360.4:c.1035G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.1035G>T​(p.Ala345Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,591,946 control chromosomes in the GnomAD database, including 121 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (68 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (53 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.70
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 11-2166492-C-A is Benign according to our data. Variant chr11-2166492-C-A is described in ClinVar as Benign. ClinVar VariationId is 304073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0513 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.1035G>T	p.Ala345Ala	synonymous	Exon 9 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1128G>T	p.Ala376Ala	synonymous	Exon 10 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1116G>T	p.Ala372Ala	synonymous	Exon 10 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.1035G>T	p.Ala345Ala	synonymous	Exon 9 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1128G>T	p.Ala376Ala	synonymous	Exon 10 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1116G>T	p.Ala372Ala	synonymous	Exon 10 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2249 AN: 152174 Hom.: 65 Cov.: 34

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00382 AC: 797 AN: 208416 AF XY: 0.00306

Gnomad AFR exome AF: 0.0534

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.000219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000368

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00173 AC: 2493 AN: 1439654 Hom.: 53 Cov.: 32 AF XY: 0.00154 AC XY: 1099 AN XY: 715452

African (AFR) AF: 0.0534 AC: 1774 AN: 33242

American (AMR) AF: 0.00336 AC: 145 AN: 43160

Ashkenazi Jewish (ASJ) AF: 0.0000776 AC: 2 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39156

South Asian (SAS) AF: 0.000905 AC: 76 AN: 83952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43344

Middle Eastern (MID) AF: 0.00279 AC: 12 AN: 4308

European-Non Finnish (NFE) AF: 0.000226 AC: 250 AN: 1107092

Other (OTH) AF: 0.00392 AC: 234 AN: 59636

GnomAD4 genome AF: 0.0150 AC: 2279 AN: 152292 Hom.: 68 Cov.: 34 AF XY: 0.0146 AC XY: 1085 AN XY: 74482

African (AFR) AF: 0.0514 AC: 2135 AN: 41566

American (AMR) AF: 0.00549 AC: 84 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68010

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00481 Hom.: 5

Bravo AF: 0.0172

Asia WGS AF: 0.00607 AC: 21 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Autosomal recessive DOPA responsive dystonia (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.2
DANN	Benign	0.88
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11826260; hg19: chr11-2187722;