7-100572740-C-A

Variant names:

• chr7-100572740-C-A
• rs777260933
• NM_001348680.2:c.523G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001348680.2(SAP25):​c.523G>T​(p.Val175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,381,776 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: 0.0000043 (0 hom.)
• Consequence: SAP25 NM_001348680.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.91

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050308913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAP25	NM_001348680.2	c.523G>T	p.Val175Leu	missense_variant	Exon 5 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3	c.502G>T	p.Val168Leu	missense_variant	Exon 5 of 6		NP_001162153.2
SAP25	NM_001348677.2	c.229G>T	p.Val77Leu	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.523G>T	p.Val175Leu	missense_variant	Exon 5 of 6	5	NM_001348680.2	ENSP00000481773.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000732 AC: 1 AN: 136686 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73514

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000434 AC: 6 AN: 1381776 Hom.: 0 Cov.: 32 AF XY: 0.00000440 AC XY: 3 AN XY: 682090

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000557

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000453 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229G>T (p.V77L) alteration is located in exon 5 (coding exon 3) of the SAP25 gene. This alteration results from a G to T substitution at nucleotide position 229, causing the valine (V) at amino acid position 77 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	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.17
DANN	Benign	0.63
DEOGEN2	Benign	0.0071	T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.26	.;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.85	N;.;.
REVEL	Benign	0.0060
Sift	Benign	0.51	T;.;.
Sift4G	Benign	0.97	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.10
MutPred		0.30		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.014
ClinPred		0.75	D
GERP RS		-4.3
Varity_R		0.023
gMVP		0.040

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

Other links and lift over

dbSNP: rs777260933; hg19: chr7-100170363;