Genetic Variant TH:c.313-38_313-35delTTCT (chr11-2168699-GAGAA-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000360.4(TH):c.313-38_313-35delTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 968,646 control chromosomes in the GnomAD database, including 362 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 41 hom., cov: 30)

Exomes 𝑓: 0.0089 ( 321 hom. )

Consequence

TH
NM_000360.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0720

Publications

0 publications found

Variant links:

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

TH links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 11-2168699-GAGAA-G is Benign according to our data. Variant chr11-2168699-GAGAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.313-38_313-35delTTCT		intron_variant	Intron 2 of 12	ENST00000352909.8	NP_000351.2	P07101-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 link	c.313-38_313-35delTTCT		intron_variant	Intron 2 of 12	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1383

AN:

133082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0213

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0512

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.0118

GnomAD2 exomes

AF:

0.0220

AC:

4504

AN:

204318

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.000441

Gnomad EAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.0357

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.0183

GnomAD4 exome

AF:

0.00893

AC:

7464

AN:

835474

Hom.:

321

AF XY:

0.00776

AC XY:

3314

AN XY:

426974

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

16788

American (AMR)

AF:

0.117

AC:

4207

AN:

35820

Ashkenazi Jewish (ASJ)

AF:

0.000332

AC:

AN:

15070

East Asian (EAS)

AF:

0.0416

AC:

686

AN:

16500

South Asian (SAS)

AF:

0.000681

AC:

AN:

71940

European-Finnish (FIN)

AF:

0.0487

AC:

1684

AN:

34610

Middle Eastern (MID)

AF:

0.000766

AC:

AN:

2612

European-Non Finnish (NFE)

AF:

0.000817

AC:

499

AN:

610518

Other (OTH)

AF:

0.00936

AC:

296

AN:

31616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

330

660

989

1319

1649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0104

AC:

1387

AN:

133172

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

797

AN XY:

63152

show subpopulations

African (AFR)

AF:

0.00319

AC:

116

AN:

36332

American (AMR)

AF:

0.0591

AC:

709

AN:

11988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3296

East Asian (EAS)

AF:

0.0216

AC:

AN:

3842

South Asian (SAS)

AF:

0.00

AC:

AN:

3738

European-Finnish (FIN)

AF:

0.0512

AC:

369

AN:

7206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

63770

Other (OTH)

AF:

0.0116

AC:

AN:

1890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00648

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 09, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.072

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over