17-8757376-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394956.1(SPDYE4):​c.226G>C​(p.Glu76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000816 in 1,594,040 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SPDYE4
NM_001394956.1 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21426737).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPDYE4NM_001394956.1 linkc.226G>C p.Glu76Gln missense_variant Exon 2 of 7 ENST00000689094.1 NP_001381885.1
SPDYE4NM_001128076.3 linkc.226G>C p.Glu76Gln missense_variant Exon 2 of 7 NP_001121548.1 A6NLX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPDYE4ENST00000689094.1 linkc.226G>C p.Glu76Gln missense_variant Exon 2 of 7 NM_001394956.1 ENSP00000509506.1 A6NLX3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
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
GnomAD4 exome
AF:
0.00000624
AC:
9
AN:
1441848
Hom.:
0
Cov.:
31
AF XY:
0.00000280
AC XY:
2
AN XY:
715204
show subpopulations
Gnomad4 AFR exome
AF:
0.000242
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:
9.07e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000965
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
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 10, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.226G>C (p.E76Q) alteration is located in exon 2 (coding exon 2) of the SPDYE4 gene. This alteration results from a G to C substitution at nucleotide position 226, causing the glutamic acid (E) at amino acid position 76 to be replaced by a glutamine (Q). 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
0.093
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
15
DANN
Benign
0.71
DEOGEN2
Benign
0.076
T
Eigen
Benign
0.018
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.85
T
M_CAP
Benign
0.0025
T
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.092
Sift
Benign
0.21
T
Sift4G
Benign
0.22
T
Polyphen
1.0
D
Vest4
0.24
MutPred
0.28
Gain of sheet (P = 0.0125);
MVP
0.20
MPC
0.17
ClinPred
0.37
T
GERP RS
2.1
Varity_R
0.094
gMVP
0.059

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: rs992218890; hg19: chr17-8660694; API