Genetic Variant SPDYE5:p.Ser133Arg (chr7-75496693-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001306141.4(SPDYE5):c.399C>A(p.Ser133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000814 in 1,597,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

SPDYE5
NM_001306141.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.872

Variant links:

Genes affected

SPDYE5 (HGNC:35464): (speedy/RINGO cell cycle regulator family member E5) Predicted to enable protein kinase binding activity. Predicted to be involved in positive regulation of cyclin-dependent protein serine/threonine kinase activity. [provided by Alliance of Genome Resources, Apr 2022]

SPDYE5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05713901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE5	NM_001306141.4 link	c.399C>A	p.Ser133Arg	missense_variant	Exon 4 of 9	ENST00000625065.4	NP_001293070.1	A6NIY4
SPDYE5	XM_047420408.1 link	c.399C>A	p.Ser133Arg	missense_variant	Exon 3 of 8		XP_047276364.1
SPDYE5	XM_047420407.1 link	c.399C>A	p.Ser133Arg	missense_variant	Exon 3 of 5		XP_047276363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDYE5	ENST00000625065.4 link	c.399C>A	p.Ser133Arg	missense_variant	Exon 4 of 9	5	NM_001306141.4	ENSP00000485398.1		A6NIY4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151734

Hom.:

Cov.:

show subpopulations

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:

0.000418

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000186

AC:

AN:

215208

Hom.:

AF XY:

0.0000256

AC XY:

AN XY:

117126

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:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000999

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000761

AC:

AN:

1445288

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719350

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151850

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74172

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:

0.000418

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000343

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.279C>A (p.S93R) alteration is located in exon 2 (coding exon 2) of the SPDYE5 gene. This alteration results from a C to A substitution at nucleotide position 279, causing the serine (S) at amino acid position 93 to be replaced by an arginine (R). 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

0.29

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

3.2

DANN

Benign

0.40

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.52

.;T;T

MetaRNN

Benign

0.057

T;T;T

PrimateAI

Uncertain

0.55

Sift4G

Benign

0.51

T;T;T

Vest4

0.064

MVP

0.030

GERP RS

-0.91

Varity_R

0.088

gMVP

0.0099

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

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