Genetic Variant SAP25:p.Arg224His (chr7-100572510-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001348680.2(SAP25):c.671G>A(p.Arg224His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,281,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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: 0.0000086 ( 0 hom. )

Consequence

SAP25
NM_001348680.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.442

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.070432216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SAP25	NM_001348680.2 link	c.671G>A	p.Arg224His	missense_variant	Exon 6 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3 link	c.650G>A	p.Arg217His	missense_variant	Exon 6 of 6		NP_001162153.2
SAP25	NM_001348677.2 link	c.377G>A	p.Arg126His	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.671G>A	p.Arg224His	missense_variant	Exon 6 of 6	5	NM_001348680.2	ENSP00000481773.2		A0A087WYF9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000858

AC:

AN:

1281366

Hom.:

Cov.:

AF XY:

0.00000643

AC XY:

AN XY:

621752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000157

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000875

Gnomad4 OTH exome

AF:

0.0000187

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377G>A (p.R126H) alteration is located in exon 6 (coding exon 4) of the SAP25 gene. This alteration results from a G to A substitution at nucleotide position 377, causing the arginine (R) at amino acid position 126 to be replaced by a histidine (H). 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

0.087

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.0047

T;.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.43

.;T;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.070

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.29

N;.;.

REVEL

Benign

0.098

Sift

Benign

0.67

T;.;.

Sift4G

Benign

0.23

T;T;T

Polyphen

0.65

P;.;P

Vest4

0.061

MutPred

0.17

Loss of methylation at R126 (P = 0.0389);.;Loss of methylation at R126 (P = 0.0389);

MVP

0.030

ClinPred

0.15

GERP RS

-1.2

Varity_R

0.021

gMVP

0.051

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over