11-2165288-C-T

Position:

• chr11-2165288-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000360.4(TH):​c.1278G>A​(p.Thr426Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,612,854 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (43 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.08

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-2165288-C-T is Benign according to our data. Variant chr11-2165288-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 304069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1939/152298) while in subpopulation AFR AF= 0.0442 (1835/41552). AF 95% confidence interval is 0.0425. There are 54 homozygotes in gnomad4. There are 905 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1278G>A	p.Thr426Thr	synonymous_variant	12/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1371G>A	p.Thr457Thr	synonymous_variant	13/14		NP_954986.2
TH	NM_199293.3	c.1359G>A	p.Thr453Thr	synonymous_variant	13/14		NP_954987.2
TH	XM_011520335.3	c.1290G>A	p.Thr430Thr	synonymous_variant	12/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1278G>A	p.Thr426Thr	synonymous_variant	12/13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1933 AN: 152180 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00339 AC: 848 AN: 250354 Hom.: 16 AF XY: 0.00246 AC XY: 334 AN XY: 135718

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00126 AC: 1847 AN: 1460556 Hom.: 43 Cov.: 32 AF XY: 0.00106 AC XY: 768 AN XY: 726568

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.0127 AC: 1939 AN: 152298 Hom.: 54 Cov.: 33 AF XY: 0.0122 AC XY: 905 AN XY: 74470

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00289 Hom.: 3

Bravo AF: 0.0151

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 03, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive DOPA responsive dystonia Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 28, 2021	- -

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 rs36097848, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.1
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs36097848; hg19: chr11-2186518;