11-2167446-C-T

Variant names:

• chr11-2167446-C-T
• rs11564716
• NM_000360.4:c.684G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000360.4(TH):​c.684G>A​(p.Glu228Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,563,192 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (66 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.856
• 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: 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.034).
• BP6: Variant 11-2167446-C-T is Benign according to our data. Variant chr11-2167446-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.856 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00681 (1038/152334) while in subpopulation NFE AF = 0.00969 (659/68032). AF 95% confidence interval is 0.00907. There are 12 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.684G>A	p.Glu228Glu	synonymous	Exon 6 of 13	NP_000351.2
	TH	NM_199292.3		c.777G>A	p.Glu259Glu	synonymous	Exon 7 of 14	NP_954986.2
	TH	NM_199293.3		c.765G>A	p.Glu255Glu	synonymous	Exon 7 of 14	NP_954987.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.684G>A	p.Glu228Glu	synonymous	Exon 6 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.777G>A	p.Glu259Glu	synonymous	Exon 7 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.765G>A	p.Glu255Glu	synonymous	Exon 7 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1038 AN: 152216 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00809

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00559 AC: 970 AN: 173630 AF XY: 0.00524

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00393

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00929

Gnomad NFE exome AF: 0.00918

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00882 AC: 12440 AN: 1410858 Hom.: 66 Cov.: 33 AF XY: 0.00855 AC XY: 5961 AN XY: 696986

African (AFR) AF: 0.00120 AC: 39 AN: 32454

American (AMR) AF: 0.00364 AC: 136 AN: 37386

Ashkenazi Jewish (ASJ) AF: 0.00412 AC: 104 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 37222

South Asian (SAS) AF: 0.000612 AC: 49 AN: 80108

European-Finnish (FIN) AF: 0.00852 AC: 414 AN: 48602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.0104 AC: 11275 AN: 1085672

Other (OTH) AF: 0.00724 AC: 423 AN: 58456

GnomAD4 genome AF: 0.00681 AC: 1038 AN: 152334 Hom.: 12 Cov.: 33 AF XY: 0.00655 AC XY: 488 AN XY: 74480

African (AFR) AF: 0.00149 AC: 62 AN: 41574

American (AMR) AF: 0.00483 AC: 74 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00809 AC: 86 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 68032

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00712 Hom.: 4

Bravo AF: 0.00655

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Autosomal recessive DOPA responsive dystonia (5)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.8
DANN	Benign	0.93
PhyloP100		0.86
Mutation Taster		=99/1	polymorphism

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: rs11564716; hg19: chr11-2188676;