NM_000360.4:c.1401C>T

Variant names:

• chr11-2164326-G-A
• rs3842724
• NM_000360.4:c.1401C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.1401C>T​(p.Asp467Asp) 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
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.1401C>T	p.Asp467Asp	synonymous	Exon 13 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1494C>T	p.Asp498Asp	synonymous	Exon 14 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1482C>T	p.Asp494Asp	synonymous	Exon 14 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.1401C>T	p.Asp467Asp	synonymous	Exon 13 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1494C>T	p.Asp498Asp	synonymous	Exon 14 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1482C>T	p.Asp494Asp	synonymous	Exon 14 of 14	ENSP00000370567.1	P07101-2

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

GnomAD2 exomes AF: 0.00690 AC: 1374 AN: 199126 AF XY: 0.00513

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 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

African (AFR) AF: 0.0779 AC: 2364 AN: 30356

American (AMR) AF: 0.00593 AC: 215 AN: 36234

Ashkenazi Jewish (ASJ) AF: 0.00339 AC: 77 AN: 22694

East Asian (EAS) AF: 0.00 AC: 0 AN: 36668

South Asian (SAS) AF: 0.000259 AC: 20 AN: 77274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50414

Middle Eastern (MID) AF: 0.00970 AC: 53 AN: 5466

European-Non Finnish (NFE) AF: 0.000825 AC: 885 AN: 1072092

Other (OTH) AF: 0.00644 AC: 368 AN: 57178

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

African (AFR) AF: 0.0795 AC: 3303 AN: 41572

American (AMR) AF: 0.0169 AC: 259 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

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

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68022

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0121 Hom.: 42

Bravo AF: 0.0278

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive DOPA responsive dystonia (3)
-	-	3	not provided (3)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.43
DANN	Benign	0.86
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs3842724; hg19: chr11-2185556;