NM_017775.4:c.1A>C

Variant names:

• chr17-15999849-A-C
• rs749196122
• NM_017775.4:c.1A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_017775.4(TTC19):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC19 NM_017775.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 108 codons. Genomic position: 16001924. Lost 0.282 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017775.4. 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.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	NP_060245.3
	TTC19	NM_001271420.2		c.-458A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001258349.1
	TTC19	NM_001271420.2		c.-458A>C		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.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000261647.5	Q6DKK2
	TTC19	ENST00000873205.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000543264.1
	TTC19	ENST00000873204.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000543263.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Benign	0.72
DEOGEN2	Benign	0.0052	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.051
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.17	T
PhyloP100		0.11
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.57
MutPred		0.84		Gain of helix (P = 0.0854)
MVP		0.59
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.55

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: rs749196122; hg19: chr17-15903163;