17-16029084-A-G

Variant names:

• chr17-16029084-A-G
• rs749875042
• NM_017775.4:c.*1562A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_017775.4(TTC19):​c.*1562A>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 0.000599 in 452,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: TTC19 NM_017775.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.469

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000599 (91/152032) while in subpopulation NFE AF= 0.00115 (78/67960). AF 95% confidence interval is 0.000942. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC19	NM_017775.4	c.*1562A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000261647.10	NP_060245.3
TTC19	NM_001271420.2	c.*1562A>G		3_prime_UTR_variant	Exon 10 of 10		NP_001258349.1
TTC19	XM_017024801.3	c.994+2382A>G		intron_variant	Intron 9 of 9		XP_016880290.2
TTC19	XM_017024802.3	c.994+2382A>G		intron_variant	Intron 9 of 9		XP_016880291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC19	ENST00000261647.10	c.*1562A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_017775.4	ENSP00000261647.5

Frequencies

GnomAD3 genomes AF: 0.000599 AC: 91 AN: 152032 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000498 AC: 63 AN: 126476 Hom.: 0 AF XY: 0.000635 AC XY: 44 AN XY: 69268

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000908

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000599 AC: 180 AN: 300344 Hom.: 0 Cov.: 0 AF XY: 0.000579 AC XY: 99 AN XY: 171130

Gnomad4 AFR exome AF: 0.000353

Gnomad4 AMR exome AF: 0.000185

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.0000812

Gnomad4 NFE exome AF: 0.000966

Gnomad4 OTH exome AF: 0.000643

GnomAD4 genome AF: 0.000599 AC: 91 AN: 152032 Hom.: 0 Cov.: 31 AF XY: 0.000471 AC XY: 35 AN XY: 74274

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000682 Hom.: 0

Bravo AF: 0.000461

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 2 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.5
DANN	Benign	0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749875042; hg19: chr17-15932398;