NM_001348680.2:c.608A>C

Variant names:

• chr7-100572655-T-G
• NM_001348680.2:c.608A>C

Variant summary

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

The NM_001348680.2(SAP25):​c.608A>C​(p.Gln203Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAP25 NM_001348680.2 missense, splice_region
• Scores: Splicing: ADA: 0.8048
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.891
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAP25	NM_001348680.2	c.608A>C	p.Gln203Pro	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000622764.3	NP_001335609.1
SAP25	NM_001168682.3	c.587A>C	p.Gln196Pro	missense_variant, splice_region_variant	Exon 5 of 6		NP_001162153.2
SAP25	NM_001348677.2	c.314A>C	p.Gln105Pro	missense_variant, splice_region_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.608A>C	p.Gln203Pro	missense_variant, splice_region_variant	Exon 5 of 6	5	NM_001348680.2	ENSP00000481773.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314A>C (p.Q105P) alteration is located in exon 5 (coding exon 3) of the SAP25 gene. This alteration results from a A to C substitution at nucleotide position 314, causing the glutamine (Q) at amino acid position 105 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	0.21
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	.;T;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.5	L;.;L
PhyloP100		0.89
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.1	D;.;.
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;.;.
Sift4G	Benign	0.19	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.60
MutPred		0.15		Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);
MVP		0.092
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.50
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.030		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

hg19: chr7-100170278;