7-100572880-T-C

Variant names:

• chr7-100572880-T-C
• rs994051311
• NM_001348680.2:c.491A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001348680.2(SAP25):​c.491A>G​(p.Gln164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000478 in 1,463,330 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: SAP25 NM_001348680.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.289
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06968215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAP25	NM_001348680.2	c.491A>G	p.Gln164Arg	missense_variant	Exon 4 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3	c.470A>G	p.Gln157Arg	missense_variant	Exon 4 of 6		NP_001162153.2
SAP25	NM_001348677.2	c.197A>G	p.Gln66Arg	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.491A>G	p.Gln164Arg	missense_variant	Exon 4 of 6	5	NM_001348680.2	ENSP00000481773.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152016 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000381 AC: 5 AN: 1311314 Hom.: 0 Cov.: 32 AF XY: 0.00000469 AC XY: 3 AN XY: 640306

African (AFR) AF: 0.00 AC: 0 AN: 28760

American (AMR) AF: 0.00 AC: 0 AN: 23016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20070

East Asian (EAS) AF: 0.00 AC: 0 AN: 35118

South Asian (SAS) AF: 0.00 AC: 0 AN: 68326

European-Finnish (FIN) AF: 0.0000316 AC: 1 AN: 31676

Middle Eastern (MID) AF: 0.000377 AC: 2 AN: 5308

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1044456

Other (OTH) AF: 0.00 AC: 0 AN: 54584

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74252

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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: 0.0000294 AC: 2 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.197A>G (p.Q66R) alteration is located in exon 4 (coding exon 2) of the SAP25 gene. This alteration results from a A to G substitution at nucleotide position 197, causing the glutamine (Q) at amino acid position 66 to be replaced by an arginine (R). 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	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.029	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.34	.;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;L
PhyloP100		-0.29
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N;.;.
REVEL	Benign	0.034
Sift	Benign	0.050	D;.;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.22	B;.;B
Vest4		0.056
MutPred		0.17		Loss of solvent accessibility (P = 0.1279);.;Loss of solvent accessibility (P = 0.1279);
MVP		0.014
ClinPred		0.092	T
GERP RS		1.8
Varity_R		0.059
gMVP		0.038
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs994051311; hg19: chr7-100170503;