rs371163842

Variant names:

• chr7-100572988-G-A
• rs371163842
• NM_001348680.2:c.383C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001348680.2(SAP25):​c.383C>T​(p.Ser128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000307 in 1,499,468 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: SAP25 NM_001348680.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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]

ENSG00000274272 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27905384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAP25	NM_001348680.2	c.383C>T	p.Ser128Leu	missense_variant	Exon 4 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3	c.362C>T	p.Ser121Leu	missense_variant	Exon 4 of 6		NP_001162153.2
SAP25	NM_001348677.2	c.89C>T	p.Ser30Leu	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	c.383C>T	p.Ser128Leu	missense_variant	Exon 4 of 6	5	NM_001348680.2	ENSP00000481773.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000369 AC: 4 AN: 108468 AF XY: 0.0000348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000211

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000234

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000304 AC: 41 AN: 1347414 Hom.: 1 Cov.: 32 AF XY: 0.0000257 AC XY: 17 AN XY: 661708

African (AFR) AF: 0.00 AC: 0 AN: 30320

American (AMR) AF: 0.0000334 AC: 1 AN: 29920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22510

East Asian (EAS) AF: 0.000198 AC: 7 AN: 35384

South Asian (SAS) AF: 0.0000268 AC: 2 AN: 74662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059504

Other (OTH) AF: 0.000535 AC: 30 AN: 56108

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89C>T (p.S30L) 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 89, causing the serine (S) at amino acid position 30 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	0.24
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	0.082
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.83	.;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;L
PhyloP100		1.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.7	D;.;.
REVEL	Benign	0.074
Sift	Uncertain	0.0040	D;.;.
Sift4G	Uncertain	0.0080	D;T;D
Polyphen		0.99	D;.;D
Vest4		0.58
MutPred		0.28		Loss of disorder (P = 0.019);.;Loss of disorder (P = 0.019);
MVP		0.18
ClinPred		0.38	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.20
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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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Other links and lift over

dbSNP: rs371163842; hg19: chr7-100170611;