Genetic Variant NM_001145250.2:c.746C>A (chr2-174336831-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001145250.2(SP9):c.746C>A(p.Ser249Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S249A) 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: 2.70

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 3 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.

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.746C>A	p.Ser249Tyr	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.746C>A	p.Ser249Tyr	missense	Exon 2 of 2	ENSP00000378418.2	P0CG40
ENSG00000280414	ENST00000624790.1	TSL:6	n.736G>T		non_coding_transcript_exon	Exon 1 of 1
LINC01305	ENST00000823786.1		n.619-4255C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1374306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678430

African (AFR)

AF:

0.00

AC:

AN:

29826

American (AMR)

AF:

0.00

AC:

AN:

34924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24768

East Asian (EAS)

AF:

0.00

AC:

AN:

34374

South Asian (SAS)

AF:

0.00

AC:

AN:

77954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074836

Other (OTH)

AF:

0.00

AC:

AN:

57570

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

Pathogenic

0.68

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

2.7

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.13

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.052

Polyphen

0.98

Vest4

0.19

MutPred

0.40

Gain of sheet (P = 0.0166)

MVP

0.15

MPC

2.6

ClinPred

0.94

GERP RS

3.1

Varity_R

0.68

gMVP

0.66

Mutation Taster

=41/59

disease causing

(source)

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

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