Genetic Variant NM_001348680.2:c.422C>T (chr7-100572949-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001348680.2(SAP25):c.422C>T(p.Pro141Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,356,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SAP25
NM_001348680.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.18

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SAP25	NM_001348680.2 link	c.422C>T	p.Pro141Leu	missense_variant	Exon 4 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3 link	c.401C>T	p.Pro134Leu	missense_variant	Exon 4 of 6		NP_001162153.2
SAP25	NM_001348677.2 link	c.128C>T	p.Pro43Leu	missense_variant	Exon 3 of 5		NP_001335606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAP25	ENST00000622764.3 link	c.422C>T	p.Pro141Leu	missense_variant	Exon 4 of 6	5	NM_001348680.2	ENSP00000481773.2		A0A087WYF9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000842

AC:

AN:

118774

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000295

AC:

AN:

1356668

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

667172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30666

American (AMR)

AF:

0.00

AC:

AN:

31722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23196

East Asian (EAS)

AF:

0.00

AC:

AN:

35480

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1064116

Other (OTH)

AF:

0.00

AC:

AN:

56512

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.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.128C>T (p.P43L) alteration is located in exon 4 (coding exon 2) of the SAP25 gene. This alteration results from a C to T substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a leucine (L). 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

0.31

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.70

.;T;T

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.6

L;.;L

PhyloP100

2.2

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.7

D;.;.

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.66

MutPred

0.37

Loss of loop (P = 0.0073);.;Loss of loop (P = 0.0073);

MVP

0.25

ClinPred

0.99

GERP RS

5.4

Varity_R

0.68

gMVP

0.32

Mutation Taster

=85/15

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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NM_001348680.2:c.422C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over