rs11267038

chr7-25124125-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018947.6(CYCS):c.-6T>G variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 1,611,606 control chromosomes in the GnomAD database, including 2,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (167 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2144 hom.)
• Consequence: CYCS NM_018947.6 splice_region, 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.696

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 7-25124125-A-C is Benign according to our data. Variant chr7-25124125-A-C is described in ClinVar as [Benign]. Clinvar id is 261063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYCS	NM_018947.6	c.-6T>G		splice_region_variant, 5_prime_UTR_variant	2/3	ENST00000305786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYCS	ENST00000305786.7	c.-6T>G		splice_region_variant, 5_prime_UTR_variant	2/3	1	NM_018947.6	P1
CYCS	ENST00000409409.5	c.-6T>G		splice_region_variant, 5_prime_UTR_variant	2/3	3		P1
CYCS	ENST00000409764.5	c.-6T>G		splice_region_variant, 5_prime_UTR_variant	3/4	3		P1
CYCS	ENST00000413447.1	c.-6T>G		splice_region_variant, 5_prime_UTR_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6084 AN: 152090 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0399 AC: 9888 AN: 247572 Hom.: 309 AF XY: 0.0399 AC XY: 5377 AN XY: 134612

Gnomad AFR exome AF: 0.00937

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.00749

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00821

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.0602

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0499 AC: 72870 AN: 1459398 Hom.: 2144 Cov.: 31 AF XY: 0.0488 AC XY: 35404 AN XY: 726172

Gnomad4 AFR exome AF: 0.00753

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00808

Gnomad4 FIN exome AF: 0.0895

Gnomad4 NFE exome AF: 0.0574

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0400 AC: 6085 AN: 152208 Hom.: 167 Cov.: 33 AF XY: 0.0404 AC XY: 3007 AN XY: 74422

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0960

Gnomad4 NFE AF: 0.0595

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0478 Hom.: 124

Bravo AF: 0.0327

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0500

EpiControl AF: 0.0468

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Thrombocytopenia 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	17
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11267038; hg19: chr7-25163744;