chr17-15999886-T-G

Variant names:

• chr17-15999886-T-G
• NM_017775.4:c.38T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001271420.2(TTC19):​c.-421T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 1,258,522 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: TTC19 NM_001271420.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716
• Publications: 0 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]

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]

ZSWIM7 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: STRONG Submitted by: King Faisal Specialist Hospital and Research Center
• ovarian dysgenesis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21749723).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271420.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC19	NM_017775.4	MANE Select	c.38T>G	p.Phe13Cys	missense	Exon 1 of 10	NP_060245.3
	TTC19	NM_001271420.2		c.-421T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001258349.1
	TTC19	NM_001271420.2		c.-421T>G		5_prime_UTR	Exon 1 of 10	NP_001258349.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC19	ENST00000261647.10	TSL:1 MANE Select	c.38T>G	p.Phe13Cys	missense	Exon 1 of 10	ENSP00000261647.5	Q6DKK2
	TTC19	ENST00000873205.1		c.38T>G	p.Phe13Cys	missense	Exon 1 of 10	ENSP00000543264.1
	TTC19	ENST00000873204.1		c.38T>G	p.Phe13Cys	missense	Exon 1 of 10	ENSP00000543263.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000238 AC: 3 AN: 1258522 Hom.: 0 Cov.: 30 AF XY: 0.00000163 AC XY: 1 AN XY: 612974

African (AFR) AF: 0.00 AC: 0 AN: 24682

American (AMR) AF: 0.00 AC: 0 AN: 15932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18348

East Asian (EAS) AF: 0.00 AC: 0 AN: 29112

South Asian (SAS) AF: 0.00 AC: 0 AN: 60626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3636

European-Non Finnish (NFE) AF: 0.00000293 AC: 3 AN: 1023940

Other (OTH) AF: 0.00 AC: 0 AN: 52016

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.77
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.72
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Vest4		0.32
MutPred		0.27		Gain of catalytic residue at L14 (P = 0.0333)
MVP		0.78
MPC		0.20
ClinPred		0.39	T
GERP RS		4.1
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.39
Mutation Taster		=98/2	polymorphism

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

hg19: chr17-15903200;