chr11-2171568-C-T

Variant names:

• chr11-2171568-C-T
• rs10840489
• NM_000360.4:c.90+129G>A

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.90+129G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 980,520 control chromosomes in the GnomAD database, including 11,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1637 hom., cov: 31)
  • Exomes 𝑓: 0.15 (9425 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.13
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 11-2171568-C-T is Benign according to our data. Variant chr11-2171568-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.216 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.90+129G>A		intron	N/A	NP_000351.2	P07101-3
	TH	NM_199292.3		c.102+117G>A		intron	N/A	NP_954986.2	P07101-1
	TH	NM_199293.3		c.90+129G>A		intron	N/A	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.90+129G>A		intron	N/A	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.102+117G>A		intron	N/A	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.90+129G>A		intron	N/A	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21884 AN: 151864 Hom.: 1628 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.145 AC: 120191 AN: 828538 Hom.: 9425 AF XY: 0.145 AC XY: 62084 AN XY: 428832

African (AFR) AF: 0.138 AC: 2900 AN: 20986

American (AMR) AF: 0.243 AC: 8391 AN: 34518

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2239 AN: 20766

East Asian (EAS) AF: 0.160 AC: 5287 AN: 33062

South Asian (SAS) AF: 0.153 AC: 10308 AN: 67498

European-Finnish (FIN) AF: 0.131 AC: 4355 AN: 33140

Middle Eastern (MID) AF: 0.100 AC: 303 AN: 3024

European-Non Finnish (NFE) AF: 0.140 AC: 81021 AN: 576714

Other (OTH) AF: 0.139 AC: 5387 AN: 38830

GnomAD4 genome AF: 0.144 AC: 21925 AN: 151982 Hom.: 1637 Cov.: 31 AF XY: 0.146 AC XY: 10844 AN XY: 74286

African (AFR) AF: 0.136 AC: 5629 AN: 41446

American (AMR) AF: 0.222 AC: 3395 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3470

East Asian (EAS) AF: 0.112 AC: 578 AN: 5148

South Asian (SAS) AF: 0.158 AC: 763 AN: 4816

European-Finnish (FIN) AF: 0.130 AC: 1380 AN: 10578

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9401 AN: 67936

Other (OTH) AF: 0.135 AC: 283 AN: 2098

Alfa AF: 0.140 Hom.: 2317

Bravo AF: 0.147

Asia WGS AF: 0.124 AC: 434 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.37
DANN	Benign	0.35
PhyloP100		-5.1
PromoterAI		-0.010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10840489; hg19: chr11-2192798;