Genetic Variant SPDYE1:p.Ala197Val (chr7-44002800-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001378423.2(SPDYE1):c.590C>T(p.Ala197Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,522,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., cov: 15)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SPDYE1
NM_001378423.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0110

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:56874):

POLR2J4 links:

ENSG00000273432 (HGNC:):

ENSG00000273432 links:

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

POLR2J4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE1	NM_001378423.2 link	c.590C>T	p.Ala197Val	missense_variant	Exon 4 of 9	ENST00000693451.1	NP_001365352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDYE1	ENST00000693451.1 link	c.590C>T	p.Ala197Val	missense_variant	Exon 4 of 9		NM_001378423.2	ENSP00000509569.1		A0A494C1S0

Frequencies

GnomAD3 genomes

AF:

0.00000926

AC:

AN:

108002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000362

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

GnomAD3 exomes

AF:

0.0000251

AC:

AN:

198846

Hom.:

AF XY:

0.0000276

AC XY:

AN XY:

108560

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000189

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1414804

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

702658

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000339

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000926

AC:

AN:

108002

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

50218

show subpopulations

Gnomad4 AFR

AF:

0.0000362

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:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000339

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.470C>T (p.A157V) alteration is located in exon 2 (coding exon 2) of the SPDYE1 gene. This alteration results from a C to T substitution at nucleotide position 470, causing the alanine (A) at amino acid position 157 to be replaced by a valine (V). 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

0.20

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.8

DANN

Benign

0.78

DEOGEN2

Benign

0.0064

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.66

M_CAP

Benign

0.00076

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

REVEL

Benign

0.045

Sift

Benign

0.25

Sift4G

Benign

0.24

Polyphen

0.68

Vest4

0.23

MutPred

0.27

Loss of disorder (P = 0.1573);

MVP

0.088

MPC

1.7

ClinPred

0.082

Varity_R

0.040

gMVP

0.069

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -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