17-8753397-A-G

Variant names:

• chr17-8753397-A-G
• rs1012028682
• NM_001394956.1:c.578T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394956.1(SPDYE4):​c.578T>C​(p.Leu193Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,446,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SPDYE4 NM_001394956.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.127

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]

ACMG classification

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=0.18765712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE4	NM_001394956.1	c.578T>C	p.Leu193Ser	missense_variant	Exon 5 of 7	ENST00000689094.1	NP_001381885.1
SPDYE4	NM_001128076.3	c.578T>C	p.Leu193Ser	missense_variant	Exon 5 of 7		NP_001121548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDYE4	ENST00000689094.1	c.578T>C	p.Leu193Ser	missense_variant	Exon 5 of 7		NM_001394956.1	ENSP00000509506.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1446430 Hom.: 0 Cov.: 37 AF XY: 0.0000111 AC XY: 8 AN XY: 717788

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: 0.0000127

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578T>C (p.L193S) alteration is located in exon 5 (coding exon 5) of the SPDYE4 gene. This alteration results from a T to C substitution at nucleotide position 578, causing the leucine (L) at amino acid position 193 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.6
DANN	Benign	0.21
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.039
Sift	Benign	0.41	T
Sift4G	Benign	0.21	T
Polyphen		0.74	P
Vest4		0.31
MutPred		0.32		Gain of disorder (P = 0.0065);
MVP		0.092
MPC		0.11
ClinPred		0.63	D
GERP RS		-0.19
Varity_R		0.11
gMVP		0.11

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

Other links and lift over

dbSNP: rs1012028682; hg19: chr17-8656715;