Variant 7-25123729-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate

The NM_018947.6(CYCS):c.290C>A(p.Ala97Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYCS
NM_018947.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.90

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

PP5

Variant 7-25123729-G-T is Pathogenic according to our data. Variant chr7-25123729-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1703823.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 linkuse as main transcript	c.290C>A	p.Ala97Asp	missense_variant	3/3	ENST00000305786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CYCS	ENST00000305786.7 linkuse as main transcript	c.290C>A	p.Ala97Asp	missense_variant	3/3	1	NM_018947.6	P1
CYCS	ENST00000409409.5 linkuse as main transcript	c.290C>A	p.Ala97Asp	missense_variant	3/3	3		P1
CYCS	ENST00000409764.5 linkuse as main transcript	c.290C>A	p.Ala97Asp	missense_variant	4/4	3		P1
CYCS	ENST00000413447.1 linkuse as main transcript	c.290C>A	p.Ala97Asp	missense_variant	4/4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.89e-7

AC:

AN:

1451274

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722364

show subpopulations

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:

0.0000231

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Thrombocytopenia 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;D;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

.;.;T;T

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

0.040

MutationAssessor

Pathogenic

3.2

M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

0.13

B;B;B;.

Vest4

0.87

MutPred

0.62

Loss of MoRF binding (P = 0.0688);Loss of MoRF binding (P = 0.0688);Loss of MoRF binding (P = 0.0688);Loss of MoRF binding (P = 0.0688);

MVP

0.92

MPC

1.2

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over