rs3744328

Positions:

• chr17-16027568-T-C
• chr17-16027568-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017775.4(TTC19):​c.*46T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,602,908 control chromosomes in the GnomAD database, including 2,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (845 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1532 hom.)
• Consequence: TTC19 NM_017775.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0240

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-16027568-T-C is Benign according to our data. Variant chr17-16027568-T-C is described in ClinVar as [Benign]. Clinvar id is 321952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC19	NM_017775.4	c.*46T>C		3_prime_UTR_variant	10/10	ENST00000261647.10	NP_060245.3
TTC19	NM_001271420.2	c.*46T>C		3_prime_UTR_variant	10/10		NP_001258349.1
TTC19	XM_017024801.3	c.994+866T>C		intron_variant			XP_016880290.2
TTC19	XM_017024802.3	c.994+866T>C		intron_variant			XP_016880291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC19	ENST00000261647.10	c.*46T>C		3_prime_UTR_variant	10/10	1	NM_017775.4	ENSP00000261647	P1

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11895 AN: 152046 Hom.: 836 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0740

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0729

GnomAD3 exomes AF: 0.0507 AC: 12647 AN: 249310 Hom.: 561 AF XY: 0.0468 AC XY: 6311 AN XY: 134878

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.0759

Gnomad SAS exome AF: 0.0518

Gnomad FIN exome AF: 0.0411

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0351 AC: 50960 AN: 1450744 Hom.: 1532 Cov.: 26 AF XY: 0.0349 AC XY: 25231 AN XY: 722360

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.0567

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.0541

Gnomad4 SAS exome AF: 0.0500

Gnomad4 FIN exome AF: 0.0405

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0461

GnomAD4 genome AF: 0.0784 AC: 11924 AN: 152164 Hom.: 845 Cov.: 32 AF XY: 0.0785 AC XY: 5843 AN XY: 74396

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0584

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0742

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0266

Gnomad4 OTH AF: 0.0716

Alfa AF: 0.0357 Hom.: 242

Bravo AF: 0.0848

Asia WGS AF: 0.0580 AC: 204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex III deficiency nuclear type 2 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.2
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3744328; hg19: chr17-15930882; COSMIC: COSV51966311; COSMIC: COSV51966311;