NM_001348680.2:c.566G>C

Variant names:

• chr7-100572697-C-G
• rs546546962
• NM_001348680.2:c.566G>C

Variant summary

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

The NM_001348680.2(SAP25):​c.566G>C​(p.Arg189Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,535,596 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SAP25 NM_001348680.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.74
• Publications: 1 publications found

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014748961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAP25	NM_001348680.2	c.566G>C	p.Arg189Pro	missense_variant	Exon 5 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3	c.545G>C	p.Arg182Pro	missense_variant	Exon 5 of 6		NP_001162153.2
SAP25	NM_001348677.2	c.272G>C	p.Arg91Pro	missense_variant	Exon 4 of 5		NP_001335606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAP25	ENST00000622764.3	c.566G>C	p.Arg189Pro	missense_variant	Exon 5 of 6	5	NM_001348680.2	ENSP00000481773.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.0000361 AC: 5 AN: 138674 AF XY: 0.0000134

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.0000409

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: 0.0000116 AC: 16 AN: 1383488 Hom.: 0 Cov.: 32 AF XY: 0.00000586 AC XY: 4 AN XY: 682774

African (AFR) AF: 0.000317 AC: 10 AN: 31554

American (AMR) AF: 0.0000281 AC: 1 AN: 35562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078270

Other (OTH) AF: 0.00 AC: 0 AN: 57858

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74372

African (AFR) AF: 0.000651 AC: 27 AN: 41492

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67946

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000896 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272G>C (p.R91P) alteration is located in exon 5 (coding exon 3) of the SAP25 gene. This alteration results from a G to C substitution at nucleotide position 272, causing the arginine (R) at amino acid position 91 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	0.096
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.017
DANN	Benign	0.61
DEOGEN2	Benign	0.0029	T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.23	.;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	N;.;N
PhyloP100		-4.7
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.070	N;.;.
REVEL	Benign	0.044
Sift	Benign	0.24	T;.;.
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.099
MutPred		0.27		Gain of catalytic residue at P90 (P = 0.0168);.;Gain of catalytic residue at P90 (P = 0.0168);
MVP		0.030
ClinPred		0.021	T
GERP RS		-9.8
Varity_R		0.12
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs546546962; hg19: chr7-100170320;