17-8757376-C-T

Variant names:

• chr17-8757376-C-T
• rs992218890
• NM_001394956.1:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394956.1(SPDYE4):​c.226G>A​(p.Glu76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPDYE4 NM_001394956.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

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]

ENSG00000297596 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2091991).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394956.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE4	NM_001394956.1	MANE Select	c.226G>A	p.Glu76Lys	missense	Exon 2 of 7	NP_001381885.1	A6NLX3
	SPDYE4	NM_001128076.3		c.226G>A	p.Glu76Lys	missense	Exon 2 of 7	NP_001121548.1	A6NLX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE4	ENST00000689094.1	MANE Select	c.226G>A	p.Glu76Lys	missense	Exon 2 of 7	ENSP00000509506.1	A6NLX3
	SPDYE4	ENST00000328794.10	TSL:1	c.226G>A	p.Glu76Lys	missense	Exon 2 of 6	ENSP00000329522.6	A6NLX3
	SPDYE4	ENST00000582989.1	TSL:1	n.*105G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000464038.1	J3QR45

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441848 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715204

African (AFR) AF: 0.00 AC: 0 AN: 33046

American (AMR) AF: 0.00 AC: 0 AN: 40566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 38990

South Asian (SAS) AF: 0.00 AC: 0 AN: 83728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102006

Other (OTH) AF: 0.00 AC: 0 AN: 59830

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.078
Sift	Benign	0.38	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.33		Gain of ubiquitination at E76 (P = 0.0048)
MVP		0.18
MPC		0.15
ClinPred		0.33	T
GERP RS		2.1
PromoterAI		-0.018	Neutral
Varity_R		0.10
gMVP		0.085

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

Other links and lift over

dbSNP: rs992218890; hg19: chr17-8660694;