Genetic Variant SPDYE3:p.Arg45His (chr7-100309001-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001004351.5(SPDYE3):c.134G>A(p.Arg45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 15)

Exomes 𝑓: 0.000096 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

SPDYE3
NM_001004351.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.277

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.066931576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE3	NM_001004351.5 link	c.134G>A	p.Arg45His	missense_variant	Exon 2 of 11	ENST00000332397.6	NP_001004351.3	A6NKU9-1
SPDYE3	XM_047420404.1 link	c.134G>A	p.Arg45His	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.134G>A	p.Arg45His	missense_variant	Exon 2 of 11	1	NM_001004351.5	ENSP00000329565.6		A6NKU9-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

118648

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000346

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000748

AC:

AN:

53484

Hom.:

AF XY:

0.0000745

AC XY:

AN XY:

26856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000668

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000955

AC:

AN:

460624

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

242110

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:

0.000913

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.0000379

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000169

AC:

AN:

118648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000346

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134G>A (p.R45H) alteration is located in exon 2 (coding exon 2) of the SPDYE3 gene. This alteration results from a G to A substitution at nucleotide position 134, causing the arginine (R) at amino acid position 45 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.6

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.30

M_CAP

Benign

0.00057

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PROVEAN

Benign

-0.080

REVEL

Benign

0.057

Sift

Benign

0.038

Sift4G

Benign

0.21

Vest4

0.080

MutPred

0.23

Loss of solvent accessibility (P = 0.0674);

MVP

0.043

MPC

1.8

ClinPred

0.049

GERP RS

0.19

Varity_R

0.053

gMVP

0.036

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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