11-2167955-G-A

Variant names:

• chr11-2167955-G-A
• rs4074905
• NM_000360.4:c.577-22C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000360.4(TH):​c.577-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,609,704 control chromosomes in the GnomAD database, including 379,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31970 hom., cov: 32)
  • Exomes 𝑓: 0.69 (347085 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0770
• Publications: 22 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 (BayesDel_noAF=-0.91).
• BP6: Variant 11-2167955-G-A is Benign according to our data. Variant chr11-2167955-G-A is described in ClinVar as Benign. ClinVar VariationId is 263257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 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.577-22C>T		intron	N/A	NP_000351.2	P07101-3
	TH	NM_199292.3		c.670-22C>T		intron	N/A	NP_954986.2	P07101-1
	TH	NM_199293.3		c.658-22C>T		intron	N/A	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.577-22C>T		intron	N/A	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.670-22C>T		intron	N/A	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.658-22C>T		intron	N/A	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96726 AN: 151952 Hom.: 31959 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.701

GnomAD2 exomes AF: 0.721 AC: 175502 AN: 243444 AF XY: 0.729

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.727

Gnomad EAS exome AF: 0.963

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.685 AC: 998979 AN: 1457636 Hom.: 347085 Cov.: 56 AF XY: 0.691 AC XY: 501018 AN XY: 724838

African (AFR) AF: 0.448 AC: 14989 AN: 33428

American (AMR) AF: 0.771 AC: 34212 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 18981 AN: 26086

East Asian (EAS) AF: 0.965 AC: 38224 AN: 39628

South Asian (SAS) AF: 0.846 AC: 72634 AN: 85896

European-Finnish (FIN) AF: 0.705 AC: 36632 AN: 51958

Middle Eastern (MID) AF: 0.837 AC: 4818 AN: 5758

European-Non Finnish (NFE) AF: 0.663 AC: 736392 AN: 1110308

Other (OTH) AF: 0.699 AC: 42097 AN: 60228

GnomAD4 genome AF: 0.636 AC: 96767 AN: 152068 Hom.: 31970 Cov.: 32 AF XY: 0.646 AC XY: 47984 AN XY: 74318

African (AFR) AF: 0.460 AC: 19093 AN: 41474

American (AMR) AF: 0.726 AC: 11099 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2532 AN: 3470

East Asian (EAS) AF: 0.955 AC: 4920 AN: 5150

South Asian (SAS) AF: 0.848 AC: 4090 AN: 4824

European-Finnish (FIN) AF: 0.707 AC: 7483 AN: 10586

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45301 AN: 67962

Other (OTH) AF: 0.705 AC: 1488 AN: 2112

Alfa AF: 0.652 Hom.: 6716

Bravo AF: 0.630

Asia WGS AF: 0.865 AC: 3007 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.73
PhyloP100		-0.077
PromoterAI		-0.0012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4074905; hg19: chr11-2189185;