rs3842724

Positions:

• chr11-2164326-G-A
• chr11-2164326-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.1401C>T​(p.Asp467=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,540,704 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (128 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (110 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-2164326-G-A is Benign according to our data. Variant chr11-2164326-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 304066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1401C>T	p.Asp467=	synonymous_variant	13/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1494C>T	p.Asp498=	synonymous_variant	14/14		NP_954986.2
TH	NM_199293.3	c.1482C>T	p.Asp494=	synonymous_variant	14/14		NP_954987.2
TH	XM_011520335.3	c.1413C>T	p.Asp471=	synonymous_variant	13/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1401C>T	p.Asp467=	synonymous_variant	13/13	1	NM_000360.4	ENSP00000325951	P1
TH	ENST00000381178.5	c.1494C>T	p.Asp498=	synonymous_variant	14/14	1		ENSP00000370571
TH	ENST00000381175.5	c.1482C>T	p.Asp494=	synonymous_variant	14/14	1		ENSP00000370567
TH	ENST00000333684.9	c.1119C>T	p.Asp373=	synonymous_variant	11/11	1		ENSP00000328814

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3680 AN: 152210 Hom.: 128 Cov.: 33

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00690 AC: 1374 AN: 199126 Hom.: 55 AF XY: 0.00513 AC XY: 553 AN XY: 107776

Gnomad AFR exome AF: 0.0811

Gnomad AMR exome AF: 0.00493

Gnomad ASJ exome AF: 0.00314

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000763

Gnomad OTH exome AF: 0.00498

GnomAD4 exome AF: 0.00287 AC: 3982 AN: 1388376 Hom.: 110 Cov.: 31 AF XY: 0.00264 AC XY: 1802 AN XY: 683680

Gnomad4 AFR exome AF: 0.0779

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.00339

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000825

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.0242 AC: 3681 AN: 152328 Hom.: 128 Cov.: 33 AF XY: 0.0231 AC XY: 1717 AN XY: 74480

Gnomad4 AFR AF: 0.0795

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0123 Hom.: 34

Bravo AF: 0.0278

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive DOPA responsive dystonia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Transient Neonatal Diabetes, Dominant/Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.43
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs3842724; hg19: chr11-2185556;