rs370429316

Variant names:

• chr11-2168615-C-T
• rs370429316
• NM_000360.4:c.363G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2168615-C-T
• chr11-2168615-C-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000360.4(TH):​c.363G>A​(p.Pro121Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,611,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.91
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-2168615-C-T is Benign according to our data. Variant chr11-2168615-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304080.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.

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.363G>A	p.Pro121Pro	synonymous	Exon 3 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.456G>A	p.Pro152Pro	synonymous	Exon 4 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.444G>A	p.Pro148Pro	synonymous	Exon 4 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.363G>A	p.Pro121Pro	synonymous	Exon 3 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.456G>A	p.Pro152Pro	synonymous	Exon 4 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.444G>A	p.Pro148Pro	synonymous	Exon 4 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152006 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000302 AC: 73 AN: 241448 AF XY: 0.000294

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000521 AC: 760 AN: 1459754 Hom.: 0 Cov.: 34 AF XY: 0.000508 AC XY: 369 AN XY: 726178

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.000224 AC: 10 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86210

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.000631 AC: 701 AN: 1111714

Other (OTH) AF: 0.000514 AC: 31 AN: 60256

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152122 Hom.: 1 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74388

African (AFR) AF: 0.000265 AC: 11 AN: 41516

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000325 Hom.: 0

Bravo AF: 0.000370

EpiCase AF: 0.000600

EpiControl AF: 0.000712

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive DOPA responsive dystonia (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.46
DANN	Benign	0.74
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs370429316; hg19: chr11-2189845;