rs1042684635

chr17-16025106-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017775.4(TTC19):c.766G>A(p.Ala256Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TTC19 NM_017775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC19	NM_017775.4	c.766G>A	p.Ala256Thr	missense_variant	8/10	ENST00000261647.10
TTC19	NM_001271420.2	c.445G>A	p.Ala149Thr	missense_variant	8/10
TTC19	XM_017024801.3	c.766G>A	p.Ala256Thr	missense_variant	8/10
TTC19	XM_017024802.3	c.766G>A	p.Ala256Thr	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC19	ENST00000261647.10	c.766G>A	p.Ala256Thr	missense_variant	8/10	1	NM_017775.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.83		Gain of phosphorylation at A256 (P = 0.0311);.;
MVP		0.94
MPC		0.61
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.63

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: rs1042684635; hg19: chr17-15928420;