7-75496755-C-T

Variant names:

• chr7-75496755-C-T
• rs781897472
• NM_001306141.4:c.461C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001306141.4(SPDYE5):​c.461C>T​(p.Ser154Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPDYE5 NM_001306141.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.26
• Publications: 0 publications found

Genes affected

SPDYE5 (HGNC:35464): (speedy/RINGO cell cycle regulator family member E5) Predicted to enable protein kinase binding activity. Predicted to be involved in positive regulation of cyclin-dependent protein serine/threonine kinase activity. [provided by Alliance of Genome Resources, Apr 2022]

PMS2P3 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.068208665).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306141.4. 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
	SPDYE5	NM_001306141.4	MANE Select	c.461C>T	p.Ser154Leu	missense	Exon 4 of 9	NP_001293070.1	A6NIY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE5	ENST00000625065.4	TSL:5 MANE Select	c.461C>T	p.Ser154Leu	missense	Exon 4 of 9	ENSP00000485398.1	A6NIY4
	PMS2P3	ENST00000845725.1		n.435-5132G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000998 AC: 15 AN: 150320 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00118

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000486 AC: 7 AN: 143914 AF XY: 0.0000520

Gnomad AFR exome AF: 0.000416

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000341

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000864 AC: 124 AN: 1434376 Hom.: 0 Cov.: 33 AF XY: 0.0000856 AC XY: 61 AN XY: 712826

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

African (AFR) AF: 0.000511 AC: 17 AN: 33256

American (AMR) AF: 0.0000236 AC: 1 AN: 42322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.000789 AC: 31 AN: 39292

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84698

European-Finnish (FIN) AF: 0.0000779 AC: 3 AN: 38534

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4120

European-Non Finnish (NFE) AF: 0.0000533 AC: 59 AN: 1106530

Other (OTH) AF: 0.000117 AC: 7 AN: 59800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000997 AC: 15 AN: 150436 Hom.: 0 Cov.: 23 AF XY: 0.000136 AC XY: 10 AN XY: 73380

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

African (AFR) AF: 0.0000976 AC: 4 AN: 40972

American (AMR) AF: 0.0000664 AC: 1 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00119 AC: 6 AN: 5056

South Asian (SAS) AF: 0.000218 AC: 1 AN: 4590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67612

Other (OTH) AF: 0.00 AC: 0 AN: 2048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000197489), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000284 AC: 3

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	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.52
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.068	T
PhyloP100		-1.3
PrimateAI	Uncertain	0.54	T
Sift4G	Uncertain	0.022	D
Vest4		0.12
MVP		0.32
Varity_R		0.069
gMVP		0.020

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: rs781897472; hg19: chr7-75126078;