chr7-25123711-G-A

Position:

• chr7-25123711-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_018947.6(CYCS):​c.308C>T​(p.Thr103Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYCS NM_018947.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.75

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Cytochrome c (size 103) in uniprot entity CYC_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_018947.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-25123711-G-A is Pathogenic according to our data. Variant chr7-25123711-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 627298.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYCS	NM_018947.6	c.308C>T	p.Thr103Ile	missense_variant	3/3	ENST00000305786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYCS	ENST00000305786.7	c.308C>T	p.Thr103Ile	missense_variant	3/3	1	NM_018947.6	P1
CYCS	ENST00000409409.5	c.308C>T	p.Thr103Ile	missense_variant	3/3	3		P1
CYCS	ENST00000409764.5	c.308C>T	p.Thr103Ile	missense_variant	4/4	3		P1
CYCS	ENST00000413447.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Thrombocytopenia 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 21, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Thrombocytopenia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.6	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.061	B;B;B
Vest4		0.60
MutPred		0.53		Loss of ubiquitination at K100 (P = 0.0413);Loss of ubiquitination at K100 (P = 0.0413);Loss of ubiquitination at K100 (P = 0.0413);
MVP		0.80
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.67

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: rs1583394618; hg19: chr7-25163330;