NM_000360.4:c.267G>A

Variant names:

• chr11-2169695-C-T
• rs76240471
• NM_000360.4:c.267G>A

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.267G>A​(p.Arg89Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,613,418 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (165 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.282
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-2169695-C-T is Benign according to our data. Variant chr11-2169695-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0566 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.267G>A	p.Arg89Arg	synonymous	Exon 2 of 13	NP_000351.2
	TH	NM_199292.3		c.360G>A	p.Arg120Arg	synonymous	Exon 3 of 14	NP_954986.2
	TH	NM_199293.3		c.348G>A	p.Arg116Arg	synonymous	Exon 3 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.267G>A	p.Arg89Arg	synonymous	Exon 2 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.360G>A	p.Arg120Arg	synonymous	Exon 3 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.348G>A	p.Arg116Arg	synonymous	Exon 3 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 800 AN: 152152 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00947 AC: 2359 AN: 249110 AF XY: 0.0114

Gnomad AFR exome AF: 0.000988

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00483

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.00656 AC: 9580 AN: 1461148 Hom.: 165 Cov.: 32 AF XY: 0.00781 AC XY: 5674 AN XY: 726866

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00519 AC: 232 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 532 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0434 AC: 3738 AN: 86226

European-Finnish (FIN) AF: 0.000170 AC: 9 AN: 52828

Middle Eastern (MID) AF: 0.0619 AC: 357 AN: 5764

European-Non Finnish (NFE) AF: 0.00366 AC: 4067 AN: 1111932

Other (OTH) AF: 0.0101 AC: 608 AN: 60388

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152270 Hom.: 16 Cov.: 33 AF XY: 0.00603 AC XY: 449 AN XY: 74458

African (AFR) AF: 0.00115 AC: 48 AN: 41562

American (AMR) AF: 0.0101 AC: 155 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 67992

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00523 Hom.: 5

Bravo AF: 0.00504

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00806

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Autosomal recessive DOPA responsive dystonia (7)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.4
DANN	Benign	0.93
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs76240471; hg19: chr11-2190925;