rs3744328

Variant names:

• chr17-16027568-T-C
• rs3744328
• ENST00000465567.1:n.1583T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000465567.1(TTC19):​n.1583T>C variant causes a non coding transcript exon 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 ENST00000465567.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0240
• Publications: 11 publications found

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]

TTC19 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex III deficiency nuclear type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TTC19	NM_017775.4	c.*46T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000261647.10	NP_060245.3
TTC19	NM_001271420.2	c.*46T>C		3_prime_UTR_variant	Exon 10 of 10		NP_001258349.1
TTC19	XM_017024801.3	c.994+866T>C		intron_variant	Intron 9 of 9		XP_016880290.2
TTC19	XM_017024802.3	c.994+866T>C		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.*46T>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_017775.4	ENSP00000261647.5

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

GnomAD2 exomes AF: 0.0507 AC: 12647 AN: 249310 AF XY: 0.0468

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 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

African (AFR) AF: 0.201 AC: 6684 AN: 33234

American (AMR) AF: 0.0567 AC: 2533 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 744 AN: 26044

East Asian (EAS) AF: 0.0541 AC: 2143 AN: 39626

South Asian (SAS) AF: 0.0500 AC: 4290 AN: 85848

European-Finnish (FIN) AF: 0.0405 AC: 2127 AN: 52566

Middle Eastern (MID) AF: 0.0503 AC: 289 AN: 5742

European-Non Finnish (NFE) AF: 0.0266 AC: 29380 AN: 1102962

Other (OTH) AF: 0.0461 AC: 2770 AN: 60032

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

African (AFR) AF: 0.190 AC: 7882 AN: 41514

American (AMR) AF: 0.0584 AC: 892 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3466

East Asian (EAS) AF: 0.0742 AC: 384 AN: 5176

South Asian (SAS) AF: 0.0541 AC: 260 AN: 4806

European-Finnish (FIN) AF: 0.0412 AC: 437 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0266 AC: 1811 AN: 68010

Other (OTH) AF: 0.0716 AC: 151 AN: 2108

Alfa AF: 0.0410 Hom.: 448

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

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial complex III deficiency nuclear type 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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
PhyloP100		-0.024
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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