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GeneBe

rs7950050

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000360.4(TH):c.210T>C(p.Ala70=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 1,612,568 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 334 hom., cov: 33)
Exomes 𝑓: 0.0042 ( 319 hom. )

Consequence

TH
NM_000360.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.491
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 11-2169752-A-G is Benign according to our data. Variant chr11-2169752-A-G is described in ClinVar as [Benign]. Clinvar id is 263253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.491 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THNM_000360.4 linkuse as main transcriptc.210T>C p.Ala70= synonymous_variant 2/13 ENST00000352909.8
THNM_199292.3 linkuse as main transcriptc.303T>C p.Ala101= synonymous_variant 3/14
THNM_199293.3 linkuse as main transcriptc.291T>C p.Ala97= synonymous_variant 3/14
THXM_011520335.3 linkuse as main transcriptc.222T>C p.Ala74= synonymous_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THENST00000352909.8 linkuse as main transcriptc.210T>C p.Ala70= synonymous_variant 2/131 NM_000360.4 P1P07101-3

Frequencies

GnomAD3 genomes
AF:
0.0361
AC:
5495
AN:
152168
Hom.:
332
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.123
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0166
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.00112
Gnomad OTH
AF:
0.0363
GnomAD3 exomes
AF:
0.0101
AC:
2483
AN:
247014
Hom.:
138
AF XY:
0.00739
AC XY:
994
AN XY:
134486
show subpopulations
Gnomad AFR exome
AF:
0.129
Gnomad AMR exome
AF:
0.00758
Gnomad ASJ exome
AF:
0.000402
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00105
Gnomad OTH exome
AF:
0.00663
GnomAD4 exome
AF:
0.00421
AC:
6145
AN:
1460282
Hom.:
319
Cov.:
37
AF XY:
0.00372
AC XY:
2699
AN XY:
726418
show subpopulations
Gnomad4 AFR exome
AF:
0.133
Gnomad4 AMR exome
AF:
0.00897
Gnomad4 ASJ exome
AF:
0.000191
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000522
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000494
Gnomad4 OTH exome
AF:
0.00988
GnomAD4 genome
AF:
0.0362
AC:
5519
AN:
152286
Hom.:
334
Cov.:
33
AF XY:
0.0346
AC XY:
2578
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.123
Gnomad4 AMR
AF:
0.0166
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00112
Gnomad4 OTH
AF:
0.0364
Alfa
AF:
0.0153
Hom.:
76
Bravo
AF:
0.0421
Asia WGS
AF:
0.0120
AC:
40
AN:
3478
EpiCase
AF:
0.00136
EpiControl
AF:
0.00124

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncNov 02, 2017- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
Cadd
Benign
0.61
Dann
Benign
0.83

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7950050; hg19: chr11-2190982; API