rs147131010

Variant names:

• chr11-2171775-G-A
• rs147131010
• NM_000360.4:c.12C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2171775-G-A
• chr11-2171775-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_000360.4(TH):​c.12C>T​(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,611,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.101
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-2171775-G-A is Benign according to our data. Variant chr11-2171775-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374422.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP7: Synonymous conserved (PhyloP=-0.101 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000234 (341/1459596) while in subpopulation MID AF = 0.00479 (27/5634). AF 95% confidence interval is 0.00338. There are 0 homozygotes in GnomAdExome4. There are 149 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.12C>T	p.Pro4Pro	synonymous_variant	Exon 1 of 13	ENST00000352909.8	NP_000351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.12C>T	p.Pro4Pro	synonymous_variant	Exon 1 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000118 AC: 29 AN: 245910 AF XY: 0.000127

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000234 AC: 341 AN: 1459596 Hom.: 0 Cov.: 31 AF XY: 0.000205 AC XY: 149 AN XY: 726224

African (AFR) AF: 0.000120 AC: 4 AN: 33466

American (AMR) AF: 0.000246 AC: 11 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86212

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51752

Middle Eastern (MID) AF: 0.00479 AC: 27 AN: 5634

European-Non Finnish (NFE) AF: 0.000252 AC: 280 AN: 1111730

Other (OTH) AF: 0.000166 AC: 10 AN: 60338

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74450

African (AFR) AF: 0.000144 AC: 6 AN: 41550

American (AMR) AF: 0.000131 AC: 2 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000196

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:1 Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

May 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TH: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.78
PhyloP100		-0.10
PromoterAI		0.061	Neutral
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: rs147131010; hg19: chr11-2193005;