7-25123715-CTTT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_018947.6(CYCS):c.301_303del(p.Lys101del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYCS NM_018947.6 inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.56

Genes affected

CYCS (HGNC:19986): (cytochrome c, somatic) This gene encodes a small heme protein that functions as a central component of the electron transport chain in mitochondria. The encoded protein associates with the inner membrane of the mitochondrion where it accepts electrons from cytochrome b and transfers them to the cytochrome oxidase complex. This protein is also involved in initiation of apoptosis. Mutations in this gene are associated with autosomal dominant nonsyndromic thrombocytopenia. Numerous processed pseudogenes of this gene are found throughout the human genome.[provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 13) in uniprot entity CYC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_018947.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018947.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-25123715-CTTT-C is Pathogenic according to our data. Variant chr7-25123715-CTTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 599385.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYCS	NM_018947.6	c.301_303del	p.Lys101del	inframe_deletion	3/3	ENST00000305786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYCS	ENST00000305786.7	c.301_303del	p.Lys101del	inframe_deletion	3/3	1	NM_018947.6	P1
CYCS	ENST00000409409.5	c.301_303del	p.Lys101del	inframe_deletion	3/3	3		P1
CYCS	ENST00000409764.5	c.301_303del	p.Lys101del	inframe_deletion	4/4	3		P1
CYCS	ENST00000413447.1	c.301_303del	p.Lys101del	inframe_deletion	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Thrombocytopenia 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs1562515878; hg19: chr7-25163334;