chr17-8756404-C-T

Variant names:

• chr17-8756404-C-T
• rs760258854
• NM_001394956.1:c.373G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001394956.1(SPDYE4):​c.373G>A​(p.Asp125Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SPDYE4 NM_001394956.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42149144).

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.373G>A	p.Asp125Asn	missense	Exon 3 of 7	NP_001381885.1	A6NLX3
	SPDYE4	NM_001128076.3		c.373G>A	p.Asp125Asn	missense	Exon 3 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.373G>A	p.Asp125Asn	missense	Exon 3 of 7	ENSP00000509506.1	A6NLX3
	SPDYE4	ENST00000328794.10	TSL:1	c.373G>A	p.Asp125Asn	missense	Exon 3 of 6	ENSP00000329522.6	A6NLX3
	SPDYE4	ENST00000582989.1	TSL:1	n.*252G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000464038.1	J3QR45

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250186 AF XY: 0.0000147

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 FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461752 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727190

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00251027), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.076	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.29
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.72		Gain of catalytic residue at D125 (P = 0.0134)
MVP		0.27
MPC		0.38
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.40
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760258854; hg19: chr17-8659722;