Genetic Variant SPDYE1:p.Arg234Leu (chr7-44005176-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001378423.2(SPDYE1):c.701G>T(p.Arg234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SPDYE1
NM_001378423.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE1	NM_001378423.2 link	c.701G>T	p.Arg234Leu	missense_variant	Exon 6 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.701G>T	p.Arg234Leu	missense_variant	Exon 6 of 9		NM_001378423.2	ENSP00000509569.1		A0A494C1S0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251144

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459700

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000176

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111822

Other (OTH)

AF:

0.00

AC:

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.581G>T (p.R194L) alteration is located in exon 4 (coding exon 4) of the SPDYE1 gene. This alteration results from a G to T substitution at nucleotide position 581, causing the arginine (R) at amino acid position 194 to be replaced by a leucine (L). 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

Pathogenic

0.67

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.0059

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.00093

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.0

PhyloP100

1.2

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.076

Sift

Uncertain

0.017

Sift4G

Uncertain

0.0020

Polyphen

0.94

Vest4

0.41

MutPred

0.83

Loss of methylation at R194 (P = 0.0343);

MVP

0.13

MPC

1.2

ClinPred

0.74

Varity_R

0.41

gMVP

0.71

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: -34

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

Publications

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chr7-44005176-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over