Genetic Variant SPDYE4:p.Glu25Lys (chr17-8758310-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001394956.1(SPDYE4):c.73G>A(p.Glu25Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,549,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

SPDYE4
NM_001394956.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.956

Publications

1 publications found

Variant links:

Genes affected

SPDYE4 (HGNC:35463): (speedy/RINGO cell cycle regulator family member E4) Predicted to enable protein kinase binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SPDYE4 links:

ENSG00000297596 (HGNC:):

ENSG00000297596 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008141756).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394956.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE4	NM_001394956.1	MANE Select	c.73G>A	p.Glu25Lys	missense	Exon 1 of 7	NP_001381885.1	A6NLX3
	SPDYE4	NM_001128076.3		c.73G>A	p.Glu25Lys	missense	Exon 1 of 7	NP_001121548.1	A6NLX3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDYE4	ENST00000689094.1	MANE Select	c.73G>A	p.Glu25Lys	missense	Exon 1 of 7	ENSP00000509506.1	A6NLX3
SPDYE4	ENST00000328794.10	TSL:1	c.73G>A	p.Glu25Lys	missense	Exon 1 of 6	ENSP00000329522.6	A6NLX3
SPDYE4	ENST00000582989.1	TSL:1	n.73G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000464038.1	J3QR45

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000103

AC:

AN:

155948

AF XY:

0.000109

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.0000730

AC:

102

AN:

1397824

Hom.:

Cov.:

AF XY:

0.0000624

AC XY:

AN XY:

689324

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

31568

American (AMR)

AF:

0.0000564

AC:

AN:

35478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25018

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35686

South Asian (SAS)

AF:

0.00

AC:

AN:

78880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.0000408

AC:

AN:

1078228

Other (OTH)

AF:

0.000103

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000526

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41498

American (AMR)

AF:

0.000589

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.000593

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000150

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.9

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0069

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.40

M_CAP

Benign

0.00088

MetaRNN

Benign

0.0081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

PhyloP100

-0.96

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

REVEL

Benign

0.0090

Sift

Benign

0.084

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.057

MVP

0.030

MPC

0.074

ClinPred

0.010

GERP RS

-5.3

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.053

gMVP

0.068

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over