11-2167451-C-T

Variant names:

• chr11-2167451-C-T
• rs536382000
• NM_000360.4:c.679G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_199292.3(TH):​c.772G>A​(p.Glu258Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000497 in 1,563,464 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E258A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (7 hom.)
• Consequence: TH NM_199292.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.34
• 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_199292.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.032366574).
• BP6: Variant 11-2167451-C-T is Benign according to our data. Variant chr11-2167451-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 550188.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000522 (737/1411202) while in subpopulation SAS AF = 0.00548 (439/80130). AF 95% confidence interval is 0.00506. There are 7 homozygotes in GnomAdExome4. There are 475 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199292.3. 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.679G>A	p.Glu227Lys	missense	Exon 6 of 13	NP_000351.2
	TH	NM_199292.3		c.772G>A	p.Glu258Lys	missense	Exon 7 of 14	NP_954986.2
	TH	NM_199293.3		c.760G>A	p.Glu254Lys	missense	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.679G>A	p.Glu227Lys	missense	Exon 6 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.772G>A	p.Glu258Lys	missense	Exon 7 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.760G>A	p.Glu254Lys	missense	Exon 7 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000987 AC: 171 AN: 173190 AF XY: 0.00137

Gnomad AFR exome AF: 0.0000986

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.000522 AC: 737 AN: 1411202 Hom.: 7 Cov.: 33 AF XY: 0.000681 AC XY: 475 AN XY: 697234

African (AFR) AF: 0.000154 AC: 5 AN: 32464

American (AMR) AF: 0.0000534 AC: 2 AN: 37448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37214

South Asian (SAS) AF: 0.00548 AC: 439 AN: 80130

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48564

Middle Eastern (MID) AF: 0.00333 AC: 19 AN: 5710

European-Non Finnish (NFE) AF: 0.000211 AC: 229 AN: 1085972

Other (OTH) AF: 0.000702 AC: 41 AN: 58444

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74448

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000490 AC: 57

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	Autosomal recessive DOPA responsive dystonia (5)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	0.083
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.066	T
Polyphen		0.79	P
Vest4		0.56
MVP		0.96
MPC		0.21
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.83
gMVP		0.76
Mutation Taster		=42/58	disease causing

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: rs536382000; hg19: chr11-2188681; COSMIC: COSV100147036; COSMIC: COSV100147036;