Genetic Variant SP9:p.Ser240Tyr (chr2-174336804-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001145250.2(SP9):c.719C>A(p.Ser240Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S240A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SP9
NM_001145250.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.796

Publications

0 publications found

Variant links:

Genes affected

SP9 (HGNC:30690): (Sp9 transcription factor) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

SP9 links:

ENSG00000280414 (HGNC:):

ENSG00000280414 links:

LINC01305 (HGNC:27690): (long intergenic non-protein coding RNA 1305)

LINC01305 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.2641 (below the threshold of 3.09). Trascript score misZ: 0.44683 (below the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.114874125).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145250.2. 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
	SP9	NM_001145250.2	MANE Select	c.719C>A	p.Ser240Tyr	missense	Exon 2 of 2	NP_001138722.1	P0CG40

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SP9	ENST00000394967.3	TSL:5 MANE Select	c.719C>A	p.Ser240Tyr	missense	Exon 2 of 2	ENSP00000378418.2	P0CG40
ENSG00000280414	ENST00000624790.1	TSL:6	n.763G>T		non_coding_transcript_exon	Exon 1 of 1
LINC01305	ENST00000823786.1		n.619-4282C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1373836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678128

African (AFR)

AF:

0.00

AC:

AN:

30032

American (AMR)

AF:

0.00

AC:

AN:

34782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24840

East Asian (EAS)

AF:

0.00

AC:

AN:

34312

South Asian (SAS)

AF:

0.00

AC:

AN:

77930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074400

Other (OTH)

AF:

0.00

AC:

AN:

57540

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.80

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.1

REVEL

Benign

0.24

Sift

Benign

0.038

Sift4G

Uncertain

0.060

Polyphen

0.0

Vest4

0.34

MutPred

0.41

Loss of glycosylation at S240 (P = 0.0051)

MVP

0.040

MPC

1.7

ClinPred

0.47

GERP RS

3.1

Varity_R

0.25

gMVP

0.52

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over