11-2166625-G-C

Variant names:

• chr11-2166625-G-C
• rs12419447
• NM_000360.4:c.977+8C>G

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.977+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,578,486 control chromosomes in the GnomAD database, including 91,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6578 hom., cov: 35)
  • Exomes 𝑓: 0.34 (85125 hom.)
• Consequence: TH NM_000360.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001468
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0860
• Publications: 14 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=-0.74).
• BP6: Variant 11-2166625-G-C is Benign according to our data. Variant chr11-2166625-G-C is described in ClinVar as Benign. ClinVar VariationId is 263250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 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.977+8C>G		splice_region intron	N/A	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1070+8C>G		splice_region intron	N/A	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1058+8C>G		splice_region 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.977+8C>G		splice_region intron	N/A	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1070+8C>G		splice_region intron	N/A	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1058+8C>G		splice_region intron	N/A	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41314 AN: 152114 Hom.: 6578 Cov.: 35

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.279 AC: 50436 AN: 180986 AF XY: 0.278

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.0376

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.335 AC: 478037 AN: 1426256 Hom.: 85125 Cov.: 78 AF XY: 0.331 AC XY: 233704 AN XY: 706218

African (AFR) AF: 0.127 AC: 4178 AN: 33008

American (AMR) AF: 0.236 AC: 9151 AN: 38768

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9224 AN: 25428

East Asian (EAS) AF: 0.0361 AC: 1378 AN: 38188

South Asian (SAS) AF: 0.171 AC: 13935 AN: 81616

European-Finnish (FIN) AF: 0.331 AC: 16240 AN: 49132

Middle Eastern (MID) AF: 0.225 AC: 1280 AN: 5690

European-Non Finnish (NFE) AF: 0.369 AC: 404464 AN: 1095326

Other (OTH) AF: 0.308 AC: 18187 AN: 59100

GnomAD4 genome AF: 0.271 AC: 41307 AN: 152230 Hom.: 6578 Cov.: 35 AF XY: 0.265 AC XY: 19748 AN XY: 74434

African (AFR) AF: 0.136 AC: 5667 AN: 41572

American (AMR) AF: 0.253 AC: 3867 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3470

East Asian (EAS) AF: 0.0432 AC: 224 AN: 5180

South Asian (SAS) AF: 0.160 AC: 772 AN: 4832

European-Finnish (FIN) AF: 0.334 AC: 3543 AN: 10608

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.367 AC: 24943 AN: 67962

Other (OTH) AF: 0.260 AC: 549 AN: 2110

Alfa AF: 0.306 Hom.: 2477

Bravo AF: 0.260

Asia WGS AF: 0.115 AC: 401 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Autosomal recessive DOPA responsive dystonia (6)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.3
DANN	Benign	0.89
PhyloP100		-0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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: rs12419447; hg19: chr11-2187855; COSMIC: COSV60767439; COSMIC: COSV60767439;