Genetic Variant SPDYE1:p.Pro128Ala (chr7-44002592-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378423.2(SPDYE1):c.382C>G(p.Pro128Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,581,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SPDYE1
NM_001378423.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.685

Publications

0 publications found

Variant links:

Genes affected

SPDYE1 (HGNC:16408): (speedy/RINGO cell cycle regulator family member E1) This gene is located at chromosome 7p13 which is close to the Williams Beuren syndrome chromosome region 7q11.23. [provided by RefSeq, Jul 2008]

SPDYE1 links:

POLR2J4 (HGNC:):

POLR2J4 links:

POLR2J4 (HGNC:28195): (RNA polymerase II subunit J4 (pseudogene))

POLR2J4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13694927).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378423.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDYE1	NM_001378423.2	MANE Select	c.382C>G	p.Pro128Ala	missense splice_region	Exon 4 of 9	NP_001365352.1	A0A494C1S0
SPDYE1	NM_175064.4		c.262C>G	p.Pro88Ala	missense splice_region	Exon 2 of 7	NP_778234.2
POLR2J4	NR_003655.3		n.489+11001G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDYE1	ENST00000693451.1	MANE Select	c.382C>G	p.Pro128Ala	missense splice_region	Exon 4 of 9	ENSP00000509569.1	A0A494C1S0
SPDYE1	ENST00000258704.3	TSL:1	c.262C>G	p.Pro88Ala	missense splice_region	Exon 2 of 7	ENSP00000258704.3	Q8NFV5
POLR2J4	ENST00000427076.5	TSL:1	n.444+11001G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149984

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000476

AC:

AN:

210116

AF XY:

0.00000876

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:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1431722

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

711088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.00

AC:

AN:

42084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25802

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

83564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

1105562

Other (OTH)

AF:

0.0000167

AC:

AN:

59712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.00000667

AC:

AN:

149984

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40660

American (AMR)

AF:

0.00

AC:

AN:

14912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.00

AC:

AN:

4656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67556

Other (OTH)

AF:

0.00

AC:

AN:

2044

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:

0.00

Hom.:

ExAC

AF:

0.0000168

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

0.079

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.055

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.69

M_CAP

Benign

0.00082

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.69

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.024

Sift

Uncertain

0.013

Sift4G

Benign

0.15

Polyphen

0.51

Vest4

0.14

MutPred

0.39

Gain of helix (P = 0.0022)

MVP

0.12

MPC

1.5

ClinPred

0.18

Varity_R

0.052

gMVP

0.0086

Mutation Taster

=94/6

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