rs121918552

Positions:

• chr7-25123996-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 16917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYCS	NM_018947.6	c.124G>A	p.Gly42Ser	missense_variant	2/3	ENST00000305786.7	NP_061820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYCS	ENST00000305786.7	c.124G>A	p.Gly42Ser	missense_variant	2/3	1	NM_018947.6	ENSP00000307786.2
CYCS	ENST00000409409.5	c.124G>A	p.Gly42Ser	missense_variant	2/3	3		ENSP00000386270.1
CYCS	ENST00000409764.5	c.124G>A	p.Gly42Ser	missense_variant	3/4	3		ENSP00000387279.1
CYCS	ENST00000413447.1	c.124G>A	p.Gly42Ser	missense_variant	3/4	3		ENSP00000416479.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Thrombocytopenia Pathogenic:1

Likely pathogenic, 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	0.79
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;.
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

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: rs121918552; hg19: chr7-25163615;