17-16029065-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017775.4(TTC19):c.*1543A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 452,778 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 31)
  • Exomes 𝑓: 0.021 (126 hom.)
• Consequence: TTC19 NM_017775.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0960

Genes affected

TTC19 (HGNC:26006): (tetratricopeptide repeat domain 19) This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2012]

NCOR1 (HGNC:7672): (nuclear receptor corepressor 1) This gene encodes a protein that mediates ligand-independent transcription repression of thyroid-hormone and retinoic-acid receptors by promoting chromatin condensation and preventing access of the transcription machinery. It is part of a complex which also includes histone deacetylases and transcriptional regulators similar to the yeast protein Sin3p. This gene is located between the Charcot-Marie-Tooth and Smith-Magenis syndrome critical regions on chromosome 17. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 17 and 20.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-16029065-A-G is Benign according to our data. Variant chr17-16029065-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 321981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0151 (2306/152222) while in subpopulation SAS AF= 0.033 (159/4824). AF 95% confidence interval is 0.0288. There are 27 homozygotes in gnomad4. There are 1212 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC19	NM_017775.4	c.*1543A>G		3_prime_UTR_variant	10/10	ENST00000261647.10
TTC19	NM_001271420.2	c.*1543A>G		3_prime_UTR_variant	10/10
TTC19	XM_017024801.3	c.994+2363A>G		intron_variant
TTC19	XM_017024802.3	c.994+2363A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC19	ENST00000261647.10	c.*1543A>G		3_prime_UTR_variant	10/10	1	NM_017775.4	P1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2303 AN: 152104 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0216 AC: 2745 AN: 126916 Hom.: 59 AF XY: 0.0208 AC XY: 1446 AN XY: 69484

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.0384

Gnomad ASJ exome AF: 0.00485

Gnomad EAS exome AF: 0.00106

Gnomad SAS exome AF: 0.0335

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0207 AC: 6219 AN: 300556 Hom.: 126 Cov.: 0 AF XY: 0.0208 AC XY: 3558 AN XY: 171226

Gnomad4 AFR exome AF: 0.00471

Gnomad4 AMR exome AF: 0.0385

Gnomad4 ASJ exome AF: 0.00456

Gnomad4 EAS exome AF: 0.00119

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0151 AC: 2306 AN: 152222 Hom.: 27 Cov.: 31 AF XY: 0.0163 AC XY: 1212 AN XY: 74418

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0148 Hom.: 2

Bravo AF: 0.0135

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	7.1
Dann	Benign	0.51

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs118174899; hg19: chr17-15932379;