2-174336966-G-A

Position:

• chr2-174336966-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001145250.2(SP9):​c.881G>A​(p.Ser294Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000392 in 1,276,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: SP9 NM_001145250.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

Genes affected

SP9 (HGNC:30690): (Sp9 transcription factor) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000280414 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1608544).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SP9	NM_001145250.2	c.881G>A	p.Ser294Asn	missense_variant	2/2	ENST00000394967.3	NP_001138722.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SP9	ENST00000394967.3	c.881G>A	p.Ser294Asn	missense_variant	2/2	5	NM_001145250.2	ENSP00000378418.2
ENSG00000280414	ENST00000624790.1	n.601C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000392 AC: 5 AN: 1276516 Hom.: 0 Cov.: 34 AF XY: 0.00000479 AC XY: 3 AN XY: 626270

Gnomad4 AFR exome AF: 0.0000398

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: 0.00000386

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.881G>A (p.S294N) alteration is located in exon 2 (coding exon 2) of the SP9 gene. This alteration results from a G to A substitution at nucleotide position 881, causing the serine (S) at amino acid position 294 to be replaced by an asparagine (N). 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	0.25
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.069
Sift	Benign	0.058	T
Sift4G	Benign	0.12	T
Polyphen		0.56	P
Vest4		0.13
MutPred		0.27		Loss of glycosylation at S294 (P = 0.0025);
MVP		0.061
MPC		1.2
ClinPred		0.73	D
GERP RS		3.0
Varity_R		0.22
gMVP		0.36

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: rs1433653134; hg19: chr2-175201694;