Genetic Variant SAP25:p.Leu288Pro (chr7-100572318-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001348680.2(SAP25):c.863T>C(p.Leu288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000845 in 1,182,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

SAP25
NM_001348680.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.319

Publications

0 publications found

Variant links:

Genes affected

SAP25 (HGNC:41908): (Sin3A associated protein 25) Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SAP25 links:

ENSG00000274272 (HGNC:):

ENSG00000274272 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06729752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SAP25	NM_001348680.2 link	c.863T>C	p.Leu288Pro	missense_variant	Exon 6 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3 link	c.842T>C	p.Leu281Pro	missense_variant	Exon 6 of 6		NP_001162153.2
SAP25	NM_001348677.2 link	c.569T>C	p.Leu190Pro	missense_variant	Exon 5 of 5		NP_001335606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAP25	ENST00000622764.3 link	c.863T>C	p.Leu288Pro	missense_variant	Exon 6 of 6	5	NM_001348680.2	ENSP00000481773.2		A0A087WYF9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.45e-7

AC:

AN:

1182768

Hom.:

Cov.:

AF XY:

0.00000177

AC XY:

AN XY:

566470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24718

American (AMR)

AF:

0.00

AC:

AN:

11860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16484

East Asian (EAS)

AF:

0.00

AC:

AN:

28432

South Asian (SAS)

AF:

0.00

AC:

AN:

42200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4908

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

977486

Other (OTH)

AF:

0.00

AC:

AN:

48688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.569T>C (p.L190P) alteration is located in exon 6 (coding exon 4) of the SAP25 gene. This alteration results from a T to C substitution at nucleotide position 569, causing the leucine (L) at amino acid position 190 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.020

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.33

.;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;L

PhyloP100

-0.32

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.3

N;.;.

REVEL

Benign

0.019

Sift

Benign

0.13

T;.;.

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0040

B;.;B

Vest4

0.18

MutPred

0.13

Gain of glycosylation at L190 (P = 0.0465);.;Gain of glycosylation at L190 (P = 0.0465);

MVP

0.048

ClinPred

0.19

GERP RS

-0.66

Varity_R

0.16

gMVP

0.090

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over