NM_001394956.1:c.437C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001394956.1(SPDYE4):​c.437C>G​(p.Ala146Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPDYE4
NM_001394956.1 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.322
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.383955).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPDYE4NM_001394956.1 linkc.437C>G p.Ala146Gly missense_variant Exon 4 of 7 ENST00000689094.1 NP_001381885.1
SPDYE4NM_001128076.3 linkc.437C>G p.Ala146Gly missense_variant Exon 4 of 7 NP_001121548.1 A6NLX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPDYE4ENST00000689094.1 linkc.437C>G p.Ala146Gly missense_variant Exon 4 of 7 NM_001394956.1 ENSP00000509506.1 A6NLX3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
251034
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135906
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460200
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726354
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.437C>G (p.A146G) alteration is located in exon 4 (coding exon 4) of the SPDYE4 gene. This alteration results from a C to G substitution at nucleotide position 437, causing the alanine (A) at amino acid position 146 to be replaced by a glycine (G). 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
Uncertain
0.43
BayesDel_addAF
Benign
-0.083
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
19
DANN
Benign
0.62
DEOGEN2
Benign
0.18
T
Eigen
Benign
-0.060
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.38
T
MetaSVM
Benign
-0.81
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.4
D
REVEL
Benign
0.27
Sift
Benign
0.030
D
Sift4G
Uncertain
0.054
T
Polyphen
1.0
D
Vest4
0.24
MutPred
0.74
Loss of stability (P = 0.042);
MVP
0.081
MPC
0.37
ClinPred
0.89
D
GERP RS
2.9
Varity_R
0.21
gMVP
0.094

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs745594798; hg19: chr17-8658886; API