11-2163956-C-T

Variant names:

• chr11-2163956-C-T
• rs3842725
• NM_000360.4:c.*277G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000360.4(TH):​c.*277G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 333,612 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: TH NM_000360.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -4.33
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 11-2163956-C-T is Benign according to our data. Variant chr11-2163956-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304062.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00522 (795/152224) while in subpopulation AFR AF = 0.0177 (734/41536). AF 95% confidence interval is 0.0166. There are 8 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.*277G>A		3_prime_UTR	Exon 13 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.*277G>A		3_prime_UTR	Exon 14 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.*277G>A		3_prime_UTR	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.*277G>A		3_prime_UTR	Exon 13 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.*277G>A		3_prime_UTR	Exon 14 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.*277G>A		3_prime_UTR	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 784 AN: 152106 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000821 AC: 149 AN: 181388 Hom.: 2 Cov.: 0 AF XY: 0.000757 AC XY: 69 AN XY: 91090

African (AFR) AF: 0.0172 AC: 98 AN: 5682

American (AMR) AF: 0.00115 AC: 6 AN: 5218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7324

East Asian (EAS) AF: 0.00 AC: 0 AN: 17048

South Asian (SAS) AF: 0.00 AC: 0 AN: 1986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14334

Middle Eastern (MID) AF: 0.00104 AC: 1 AN: 962

European-Non Finnish (NFE) AF: 0.000206 AC: 24 AN: 116360

Other (OTH) AF: 0.00160 AC: 20 AN: 12474

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152224 Hom.: 8 Cov.: 33 AF XY: 0.00496 AC XY: 369 AN XY: 74426

African (AFR) AF: 0.0177 AC: 734 AN: 41536

American (AMR) AF: 0.00242 AC: 37 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67988

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.00565

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.29
DANN	Benign	0.52
PhyloP100		-4.3
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: rs3842725; hg19: chr11-2185186;