chr11-2171771-C-T

Variant names:

• chr11-2171771-C-T
• rs74555599
• NM_000360.4:c.16G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000360.4(TH):​c.16G>A​(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,612,174 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (26 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.166
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050002337).
• BP6: Variant 11-2171771-C-T is Benign according to our data. Variant chr11-2171771-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00434 (660/152238) while in subpopulation NFE AF = 0.00557 (379/67986). AF 95% confidence interval is 0.00511. There are 4 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.16G>A	p.Ala6Thr	missense	Exon 1 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.16G>A	p.Ala6Thr	missense	Exon 1 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.16G>A	p.Ala6Thr	missense	Exon 1 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.16G>A	p.Ala6Thr	missense	Exon 1 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.16G>A	p.Ala6Thr	missense	Exon 1 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.16G>A	p.Ala6Thr	missense	Exon 1 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152120 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00422 AC: 1040 AN: 246498 AF XY: 0.00431

Gnomad AFR exome AF: 0.000681

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.00595

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00490 AC: 7150 AN: 1459936 Hom.: 26 Cov.: 31 AF XY: 0.00468 AC XY: 3396 AN XY: 726360

African (AFR) AF: 0.000747 AC: 25 AN: 33474

American (AMR) AF: 0.000403 AC: 18 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.0149 AC: 774 AN: 52022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00552 AC: 6138 AN: 1111786

Other (OTH) AF: 0.00315 AC: 190 AN: 60336

GnomAD4 genome AF: 0.00434 AC: 660 AN: 152238 Hom.: 4 Cov.: 32 AF XY: 0.00445 AC XY: 331 AN XY: 74424

African (AFR) AF: 0.000866 AC: 36 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00557 AC: 379 AN: 67986

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00450 Hom.: 6

Bravo AF: 0.00316

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00450 AC: 546

EpiCase AF: 0.00365

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	7.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0050	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.90	L
PhyloP100		-0.17
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.28
Sift	Benign	0.36	T
Sift4G	Benign	0.91	T
Polyphen		0.0040	B
Vest4		0.082
MVP		0.76
MPC		0.047
ClinPred		0.022	T
GERP RS		-1.8
PromoterAI		-0.023	Neutral
Varity_R		0.041
gMVP		0.28
Mutation Taster		=100/0	polymorphism

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: rs74555599; hg19: chr11-2193001; COSMIC: COSV99048114; COSMIC: COSV99048114;