rs121918552

Variant names:

• chr7-25123996-C-T
• rs121918552
• NM_018947.6:c.124G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_018947.6(CYCS):​c.124G>A​(p.Gly42Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYCS NM_018947.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67
• Publications: 13 publications found

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]

CYCS Gene-Disease associations (from GenCC):

• thrombocytopenia 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal thrombocytopenia with normal platelets

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296268 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a chain Cytochrome c (size 103) in uniprot entity CYC_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_018947.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.1844 (below the threshold of 3.09). Trascript score misZ: 1.3716 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombocytopenia 4, autosomal thrombocytopenia with normal platelets.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 7-25123996-C-T is Pathogenic according to our data. Variant chr7-25123996-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYCS	NM_018947.6	c.124G>A	p.Gly42Ser	missense_variant	Exon 2 of 3	ENST00000305786.7	NP_061820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYCS	ENST00000305786.7	c.124G>A	p.Gly42Ser	missense_variant	Exon 2 of 3	1	NM_018947.6	ENSP00000307786.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 4 Pathogenic:2

Feb 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Thrombocytopenia Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.1	H;H;H;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.88	P;P;P;.
Vest4		0.89
MutPred		0.81		Gain of catalytic residue at G42 (P = 0.0429);Gain of catalytic residue at G42 (P = 0.0429);Gain of catalytic residue at G42 (P = 0.0429);Gain of catalytic residue at G42 (P = 0.0429);
MVP		0.91
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.83
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs121918552; hg19: chr7-25163615;