7-25123724-G-A

Position:

• chr7-25123724-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_018947.6(CYCS):​c.295C>T​(p.Leu99Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,216 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L99V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CYCS NM_018947.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.59

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 10 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-25123724-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812966.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 7-25123724-G-A is Pathogenic according to our data. Variant chr7-25123724-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2628903.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYCS	NM_018947.6	c.295C>T	p.Leu99Phe	missense_variant	3/3	ENST00000305786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYCS	ENST00000305786.7	c.295C>T	p.Leu99Phe	missense_variant	3/3	1	NM_018947.6	P1
CYCS	ENST00000409409.5	c.295C>T	p.Leu99Phe	missense_variant	3/3	3		P1
CYCS	ENST00000409764.5	c.295C>T	p.Leu99Phe	missense_variant	4/4	3		P1
CYCS	ENST00000413447.1	c.295C>T	p.Leu99Phe	missense_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450216 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721874

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

CYCS-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

The CYCS c.295C>T variant is predicted to result in the amino acid substitution p.Leu99Phe. To our knowledge, this variant has not been reported in the literature. However, a different missense variant in the same codon (c.295C>G, p.Leu99Val) has been reported in multiple individuals with thrombocytopenia and interpreted as likely pathogenic in a cohort study with whole-genome sequencing of patients with rare diseases (Turro et al. 2020. PubMed ID: 32581362. Table S2) suggesting that substitution of amino acid residue p.Leu99 is not tolerated. At PreventionGenetics, we have detected this variant in the heterozygous state in multiple affected individuals with thrombocytopenia in a family and an unrelated individual. This variant is not reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;D;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	4.4	H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.92	P;P;P;.
Vest4		0.82
MutPred		0.66		Gain of methylation at K100 (P = 0.0272);Gain of methylation at K100 (P = 0.0272);Gain of methylation at K100 (P = 0.0272);Gain of methylation at K100 (P = 0.0272);
MVP		0.96
MPC		1.5
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-25163343;