11-2163956-C-T

Position:

• chr11-2163956-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

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: {Benign=1, Likely_benign=3, Uncertain_significance=1}.
• 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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.*277G>A		3_prime_UTR_variant	13/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.*277G>A		3_prime_UTR_variant	14/14		NP_954986.2
TH	NM_199293.3	c.*277G>A		3_prime_UTR_variant	14/14		NP_954987.2
TH	XM_011520335.3	c.*277G>A		3_prime_UTR_variant	13/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909	c.*277G>A		3_prime_UTR_variant	13/13	1	NM_000360.4	ENSP00000325951.4
TH	ENST00000381178	c.*277G>A		3_prime_UTR_variant	14/14	1		ENSP00000370571.1
TH	ENST00000381175	c.*277G>A		3_prime_UTR_variant	14/14	1		ENSP00000370567.1
TH	ENST00000333684	c.*277G>A		3_prime_UTR_variant	11/11	1		ENSP00000328814.6

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

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.: 8 Cov.: 33 AF XY: 0.00496 AC XY: 369 AN XY: 74426

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.: 0

Bravo AF: 0.00565

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neonatal insulin-dependent diabetes mellitus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2020

- -

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

Other links and lift over

dbSNP: rs3842725; hg19: chr11-2185186;