NM_000360.4:c.*277G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -4.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 304062.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=3}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.*277G>A	3_prime_UTR_variant	Exon 13 of 13	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 link	c.*277G>A	3_prime_UTR_variant	Exon 14 of 14		NP_954986.2	P07101-1P78428
TH	NM_199293.3 link	c.*277G>A	3_prime_UTR_variant	Exon 14 of 14		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 link	c.*277G>A	3_prime_UTR_variant	Exon 13 of 13		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TH	ENST00000352909 link	c.*277G>A	3_prime_UTR_variant	Exon 13 of 13	1	NM_000360.4	ENSP00000325951.4	P07101-3
TH	ENST00000381178 link	c.*277G>A	3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000370571.1	P07101-1
TH	ENST00000381175 link	c.*277G>A	3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000370567.1	P07101-2
TH	ENST00000333684 link	c.*277G>A	3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000328814.6	P07101-6

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

784

AN:

152106

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000757

AC XY:

AN XY:

91090

show subpopulations

Gnomad4 AFR exome

AF:

0.0172

Gnomad4 AMR exome

AF:

0.00115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000206

Gnomad4 OTH exome

AF:

0.00160

GnomAD4 genome

AF:

0.00522

AC:

795

AN:

152224

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0177

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000614

Hom.:

Bravo

AF:

0.00565

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neonatal insulin-dependent diabetes mellitus

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as this mutation can cause beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs3842725, yet. -

Transient Neonatal Diabetes, Dominant/Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Sep 21, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.29

DANN

Benign

0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over