chr7-102561150-C-T

Variant names:

• chr7-102561150-C-T
• rs1199767083
• NM_001396242.1:c.1184C>T

Variant summary

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

The NM_001396242.1(SPDYE2):​c.1184C>T​(p.Ala395Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 5)
  • Exomes 𝑓: 0.000036 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPDYE2 NM_001396242.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.421
• Publications: 0 publications found

Genes affected

SPDYE2 (HGNC:33841): (speedy/RINGO cell cycle regulator family member E2) Predicted to enable protein kinase binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000270249 (HGNC:):

POLR2J3 (HGNC:33853): (RNA polymerase II subunit J3) This gene is a member of the RNA polymerase II subunit 11 gene family, which includes three genes in a cluster on chromosome 7q22.1 and a pseudogene on chromosome 7p13. The founding member of this family, DNA directed RNA polymerase II polypeptide J, has been shown to encode a subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This locus produces multiple, alternatively spliced transcripts that potentially express isoforms with distinct C-termini compared to DNA directed RNA polymerase II polypeptide J. Most or all variants are spliced to include additional non-coding exons at the 3' end which makes them candidates for nonsense-mediated decay (NMD). Consequently, it is not known if this locus expresses a protein or proteins in vivo. [provided by RefSeq, Jul 2008]

POLR2J3-UPK3BL2 (HGNC:58364):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.11522815).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396242.1. 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
	SPDYE2	NM_001396242.1	MANE Select	c.1184C>T	p.Ala395Val	missense	Exon 8 of 9	NP_001383171.1	Q495Y8-1
	SPDYE2	NM_001031618.3		c.1184C>T	p.Ala395Val	missense	Exon 8 of 9	NP_001026789.2	Q495Y8-1
	POLR2J3-UPK3BL2	NR_173351.1		n.464+5847G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE2	ENST00000691607.2	MANE Select	c.1184C>T	p.Ala395Val	missense	Exon 8 of 9	ENSP00000509749.1	Q495Y8-1
	SPDYE2	ENST00000341656.5	TSL:1	c.752C>T	p.Ala251Val	missense	Exon 5 of 6	ENSP00000342628.4	Q495Y8-2
	ENSG00000270249	ENST00000514917.3	TSL:3	c.748+5432G>A		intron	N/A	ENSP00000423309.4	H0Y980

Frequencies

GnomAD3 genomes AF: 0.0000437 AC: 2 AN: 45758 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.0000919

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000359 AC: 12 AN: 334412 Hom.: 1 Cov.: 3 AF XY: 0.0000465 AC XY: 8 AN XY: 172008

African (AFR) AF: 0.000159 AC: 3 AN: 18844

American (AMR) AF: 0.00 AC: 0 AN: 14166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8788

East Asian (EAS) AF: 0.000106 AC: 2 AN: 18856

South Asian (SAS) AF: 0.0000955 AC: 3 AN: 31404

European-Finnish (FIN) AF: 0.0000759 AC: 1 AN: 13174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1344

European-Non Finnish (NFE) AF: 0.0000142 AC: 3 AN: 211004

Other (OTH) AF: 0.00 AC: 0 AN: 16832

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000437 AC: 2 AN: 45758 Hom.: 0 Cov.: 5 AF XY: 0.0000930 AC XY: 2 AN XY: 21506

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

African (AFR) AF: 0.0000919 AC: 2 AN: 21762

American (AMR) AF: 0.00 AC: 0 AN: 4014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1058

East Asian (EAS) AF: 0.00 AC: 0 AN: 1404

South Asian (SAS) AF: 0.00 AC: 0 AN: 618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14506

Other (OTH) AF: 0.00 AC: 0 AN: 500

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	Uncertain	0.45
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.42
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.066
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.036	D
Polyphen		0.97	D
Vest4		0.13
MutPred		0.27		Gain of sheet (P = 0.0477)
MVP		0.040
ClinPred		0.60	D
Varity_R		0.11
gMVP		0.020
Mutation Taster		=97/3	polymorphism

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: rs1199767083; hg19: chr7-102201597;