rs4074905

Positions:

• chr11-2167955-G-A
• chr11-2167955-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000360.4(TH):​c.577-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,609,704 control chromosomes in the GnomAD database, including 379,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31970 hom., cov: 32)
  • Exomes 𝑓: 0.69 (347085 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0770

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-2167955-G-A is Benign according to our data. Variant chr11-2167955-G-A is described in ClinVar as [Benign]. Clinvar id is 263257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2167955-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.577-22C>T		intron_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.670-22C>T		intron_variant			NP_954986.2
TH	NM_199293.3	c.658-22C>T		intron_variant			NP_954987.2
TH	XM_011520335.3	c.589-22C>T		intron_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.577-22C>T		intron_variant		1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96726 AN: 151952 Hom.: 31959 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.701

GnomAD3 exomes AF: 0.721 AC: 175502 AN: 243444 Hom.: 64938 AF XY: 0.729 AC XY: 96322 AN XY: 132206

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.727

Gnomad EAS exome AF: 0.963

Gnomad SAS exome AF: 0.851

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.685 AC: 998979 AN: 1457636 Hom.: 347085 Cov.: 56 AF XY: 0.691 AC XY: 501018 AN XY: 724838

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.771

Gnomad4 ASJ exome AF: 0.728

Gnomad4 EAS exome AF: 0.965

Gnomad4 SAS exome AF: 0.846

Gnomad4 FIN exome AF: 0.705

Gnomad4 NFE exome AF: 0.663

Gnomad4 OTH exome AF: 0.699

GnomAD4 genome AF: 0.636 AC: 96767 AN: 152068 Hom.: 31970 Cov.: 32 AF XY: 0.646 AC XY: 47984 AN XY: 74318

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.726

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.955

Gnomad4 SAS AF: 0.848

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.705

Alfa AF: 0.652 Hom.: 6716

Bravo AF: 0.630

Asia WGS AF: 0.865 AC: 3007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 86. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive DOPA responsive dystonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.73

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: rs4074905; hg19: chr11-2189185;