Genetic Variant SPDYE4:p.Ala74Asp (chr17-8757381-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001394956.1(SPDYE4):c.221C>A(p.Ala74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000064 in 1,592,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

SPDYE4
NM_001394956.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.211

Publications

0 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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05641517).

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.221C>A	p.Ala74Asp	missense	Exon 2 of 7	NP_001381885.1	A6NLX3
	SPDYE4	NM_001128076.3		c.221C>A	p.Ala74Asp	missense	Exon 2 of 7	NP_001121548.1	A6NLX3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDYE4	ENST00000689094.1	MANE Select	c.221C>A	p.Ala74Asp	missense	Exon 2 of 7	ENSP00000509506.1	A6NLX3
SPDYE4	ENST00000328794.10	TSL:1	c.221C>A	p.Ala74Asp	missense	Exon 2 of 6	ENSP00000329522.6	A6NLX3
SPDYE4	ENST00000582989.1	TSL:1	n.*100C>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000464038.1	J3QR45

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000423

AC:

AN:

212712

AF XY:

0.0000350

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000694

AC:

100

AN:

1440810

Hom.:

Cov.:

AF XY:

0.0000616

AC XY:

AN XY:

714536

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

33030

American (AMR)

AF:

0.00

AC:

AN:

40368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25696

East Asian (EAS)

AF:

0.00

AC:

AN:

38952

South Asian (SAS)

AF:

0.00

AC:

AN:

83592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000862

AC:

AN:

1101462

Other (OTH)

AF:

0.0000669

AC:

AN:

59790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000282

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.0000166

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

0.090

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.81

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.0087

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.35

M_CAP

Benign

0.00066

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

PhyloP100

-0.21

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

REVEL

Benign

0.17

Sift

Benign

0.15

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.093

MVP

0.072

MPC

0.10

ClinPred

0.058

GERP RS

-3.9

PromoterAI

0.012

Neutral

(source)

Varity_R

0.078

gMVP

0.040

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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