NM_000360.4:c.720G>A

Variant names:

• chr11-2167008-C-T
• rs6357
• NM_000360.4:c.720G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.720G>A​(p.Lys240Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,585,578 control chromosomes in the GnomAD database, including 69,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4911 hom., cov: 34)
  • Exomes 𝑓: 0.29 (64681 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.75
• Publications: 27 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-2167008-C-T is Benign according to our data. Variant chr11-2167008-C-T is described in ClinVar as Benign. ClinVar VariationId is 263258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 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.720G>A	p.Lys240Lys	synonymous	Exon 7 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.813G>A	p.Lys271Lys	synonymous	Exon 8 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.801G>A	p.Lys267Lys	synonymous	Exon 8 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.720G>A	p.Lys240Lys	synonymous	Exon 7 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.813G>A	p.Lys271Lys	synonymous	Exon 8 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.801G>A	p.Lys267Lys	synonymous	Exon 8 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35758 AN: 152102 Hom.: 4911 Cov.: 34

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.229 AC: 46358 AN: 202788 AF XY: 0.229

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.0351

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.290 AC: 416356 AN: 1433358 Hom.: 64681 Cov.: 60 AF XY: 0.286 AC XY: 203524 AN XY: 710460

African (AFR) AF: 0.118 AC: 3899 AN: 32934

American (AMR) AF: 0.168 AC: 6907 AN: 41158

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6433 AN: 25540

East Asian (EAS) AF: 0.0341 AC: 1305 AN: 38298

South Asian (SAS) AF: 0.146 AC: 12013 AN: 82238

European-Finnish (FIN) AF: 0.291 AC: 14573 AN: 50054

Middle Eastern (MID) AF: 0.128 AC: 731 AN: 5722

European-Non Finnish (NFE) AF: 0.323 AC: 355109 AN: 1098104

Other (OTH) AF: 0.259 AC: 15386 AN: 59310

GnomAD4 genome AF: 0.235 AC: 35751 AN: 152220 Hom.: 4911 Cov.: 34 AF XY: 0.230 AC XY: 17107 AN XY: 74426

African (AFR) AF: 0.127 AC: 5280 AN: 41560

American (AMR) AF: 0.197 AC: 3018 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 876 AN: 3472

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5176

South Asian (SAS) AF: 0.143 AC: 689 AN: 4832

European-Finnish (FIN) AF: 0.291 AC: 3080 AN: 10602

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21732 AN: 67962

Other (OTH) AF: 0.204 AC: 430 AN: 2112

Alfa AF: 0.277 Hom.: 10740

Bravo AF: 0.222

Asia WGS AF: 0.102 AC: 356 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Autosomal recessive DOPA responsive dystonia (6)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs6357; hg19: chr11-2188238; COSMIC: COSV60767253; COSMIC: COSV60767253;