Genetic Variant SAP25:p.Ser259Cys (chr7-100572405-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001348680.2(SAP25):c.776C>G(p.Ser259Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,408,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SAP25
NM_001348680.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.235

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0616436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SAP25	NM_001348680.2 link	c.776C>G	p.Ser259Cys	missense_variant	Exon 6 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3 link	c.755C>G	p.Ser252Cys	missense_variant	Exon 6 of 6		NP_001162153.2
SAP25	NM_001348677.2 link	c.482C>G	p.Ser161Cys	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.776C>G	p.Ser259Cys	missense_variant	Exon 6 of 6	5	NM_001348680.2	ENSP00000481773.2		A0A087WYF9

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000403

AC:

AN:

49678

AF XY:

0.0000411

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000858

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

181

AN:

1255820

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

606604

show subpopulations

African (AFR)

AF:

0.0000370

AC:

AN:

27022

American (AMR)

AF:

0.000122

AC:

AN:

16424

Ashkenazi Jewish (ASJ)

AF:

0.0000551

AC:

AN:

18142

East Asian (EAS)

AF:

0.00

AC:

AN:

32008

South Asian (SAS)

AF:

0.0000683

AC:

AN:

58566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30344

Middle Eastern (MID)

AF:

0.000210

AC:

AN:

4764

European-Non Finnish (NFE)

AF:

0.000144

AC:

146

AN:

1016452

Other (OTH)

AF:

0.000499

AC:

AN:

52098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000118

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41536

American (AMR)

AF:

0.000196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000551

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.482C>G (p.S161C) alteration is located in exon 6 (coding exon 4) of the SAP25 gene. This alteration results from a C to G substitution at nucleotide position 482, causing the serine (S) at amino acid position 161 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.024

T;.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.41

.;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.062

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

L;.;L

PhyloP100

0.23

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.5

D;.;.

REVEL

Benign

0.055

Sift

Uncertain

0.0090

D;.;.

Sift4G

Uncertain

0.051

T;T;T

Polyphen

0.020

B;.;B

Vest4

0.20

MutPred

0.22

Loss of phosphorylation at S161 (P = 0.0036);.;Loss of phosphorylation at S161 (P = 0.0036);

MVP

0.014

ClinPred

0.060

GERP RS

-0.35

Varity_R

0.13

gMVP

0.11

Mutation Taster

=100/0

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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7-100572405-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over