chr11-2167458-G-A

Variant names:

• chr11-2167458-G-A
• rs1554923218
• NM_000360.4:c.672C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_000360.4(TH):​c.672C>T​(p.Tyr224Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,066 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.87
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.188).
• BP6: Variant 11-2167458-G-A is Benign according to our data. Variant chr11-2167458-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1078157.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.672C>T	p.Tyr224Tyr	synonymous	Exon 6 of 13	NP_000351.2
	TH	NM_199292.3		c.765C>T	p.Tyr255Tyr	synonymous	Exon 7 of 14	NP_954986.2
	TH	NM_199293.3		c.753C>T	p.Tyr251Tyr	synonymous	Exon 7 of 14	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.672C>T	p.Tyr224Tyr	synonymous	Exon 6 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.765C>T	p.Tyr255Tyr	synonymous	Exon 7 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.753C>T	p.Tyr251Tyr	synonymous	Exon 7 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412066 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 697742

African (AFR) AF: 0.00 AC: 0 AN: 32502

American (AMR) AF: 0.00 AC: 0 AN: 37576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00 AC: 0 AN: 37340

South Asian (SAS) AF: 0.00 AC: 0 AN: 80198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086402

Other (OTH) AF: 0.00 AC: 0 AN: 58462

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.1
DANN	Benign	0.91
PhyloP100		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554923218; hg19: chr11-2188688;