17-15999848-C-T

Variant names:

• chr17-15999848-C-T
• rs2302414
• NM_017775.4:c.-1C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017775.4(TTC19):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00092 in 1,520,784 control chromosomes in the GnomAD database, including 23 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 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (20 hom.)
• Consequence: TTC19 NM_017775.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.142

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]

ZSWIM7 (HGNC:26993): (zinc finger SWIM-type containing 7) Predicted to enable zinc ion binding activity. Involved in double-strand break repair via homologous recombination and protein stabilization. Part of Shu complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-15999848-C-T is Benign according to our data. Variant chr17-15999848-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137773.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0011 (167/152224) while in subpopulation EAS AF= 0.0261 (135/5172). AF 95% confidence interval is 0.0225. There are 3 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC19	NM_017775.4	c.-1C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000261647.10	NP_060245.3
ZSWIM7	NM_001042697.2	c.-254G>A		upstream_gene_variant		ENST00000399277.6	NP_001036162.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC19	ENST00000261647	c.-1C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_017775.4	ENSP00000261647.5
ZSWIM7	ENST00000399277.6	c.-254G>A		upstream_gene_variant		1	NM_001042697.2	ENSP00000382218.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152112 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00278 AC: 328 AN: 118166 Hom.: 8 AF XY: 0.00272 AC XY: 179 AN XY: 65840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.0279

Gnomad SAS exome AF: 0.00205

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.000900 AC: 1232 AN: 1368560 Hom.: 20 Cov.: 31 AF XY: 0.000892 AC XY: 602 AN XY: 675240

Gnomad4 AFR exome AF: 0.0000345

Gnomad4 AMR exome AF: 0.000204

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.0240

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.0000295

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152224 Hom.: 3 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74446

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0261

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 2 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Feb 19, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2302414; hg19: chr17-15903162;