Genetic Variant SPDYE3:p.Arg45Cys (chr7-100309000-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001004351.5(SPDYE3):c.133C>T(p.Arg45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00042 ( 1 hom., cov: 15)

Exomes 𝑓: 0.00063 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

SPDYE3
NM_001004351.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.65

Variant links:

Genes affected

SPDYE3 (HGNC:35462): (speedy/RINGO cell cycle regulator family member E3) Predicted to enable protein kinase binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SPDYE3 links:

ENSG00000291178 (HGNC:):

ENSG00000291178 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005124122).

BP6

Variant 7-100309000-C-T is Benign according to our data. Variant chr7-100309000-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2348592.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE3	NM_001004351.5 link	c.133C>T	p.Arg45Cys	missense_variant	Exon 2 of 11	ENST00000332397.6	NP_001004351.3	A6NKU9-1
SPDYE3	XM_047420404.1 link	c.133C>T	p.Arg45Cys	missense_variant	Exon 2 of 10		XP_047276360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDYE3	ENST00000332397.6 link	c.133C>T	p.Arg45Cys	missense_variant	Exon 2 of 11	1	NM_001004351.5	ENSP00000329565.6		A6NKU9-1

Frequencies

GnomAD3 genomes

AF:

0.000439

AC:

AN:

118486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000173

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00202

AC:

108

AN:

53350

Hom.:

AF XY:

0.00190

AC XY:

AN XY:

26812

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0128

Gnomad SAS exome

AF:

0.000501

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000540

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000632

AC:

290

AN:

459080

Hom.:

Cov.:

AF XY:

0.000626

AC XY:

151

AN XY:

241332

show subpopulations

Gnomad4 AFR exome

AF:

0.000396

Gnomad4 AMR exome

AF:

0.000369

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00782

Gnomad4 SAS exome

AF:

0.000435

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000179

Gnomad4 OTH exome

AF:

0.000342

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000422

AC:

AN:

118550

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

AN XY:

55332

show subpopulations

Gnomad4 AFR

AF:

0.0000650

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0111

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000173

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000642

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 03, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

4.1

DANN

Benign

0.10

DEOGEN2

Benign

0.0038

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.29

M_CAP

Benign

0.00080

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PROVEAN

Benign

0.67

REVEL

Benign

0.052

Sift

Benign

0.20

Sift4G

Benign

0.14

Vest4

0.13

MutPred

0.24

Loss of solvent accessibility (P = 0.0561);

MVP

0.043

MPC

1.8

ClinPred

0.013

GERP RS

-0.38

Varity_R

0.071

gMVP

0.038

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over