rs2487999

Variant names:

• chr10-103900068-T-A
• rs2487999
• NM_024928.5:c.451A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-103900068-T-A
• chr10-103900068-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024928.5(STN1):​c.451A>T​(p.Thr151Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T151A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: STN1 NM_024928.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.54
• Publications: 74 publications found

Genes affected

STN1 (HGNC:26200): (STN1 subunit of CST complex) OBFC1 and C17ORF68 (MIM 613129) are subunits of an alpha accessory factor (AAF) that stimulates the activity of DNA polymerase-alpha-primase (see MIM 176636), the enzyme that initiates DNA replication (Casteel et al., 2009 [PubMed 19119139]). OBFC1 also appears to function in a telomere-associated complex with C17ORF68 and TEN1 (C17ORF106; MIM 613130) (Miyake et al., 2009 [PubMed 19854130]).[supplied by OMIM, Nov 2009]

STN1 Gene-Disease associations (from GenCC):

• cerebroretinal microangiopathy with calcifications and cysts 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Coats plus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289744 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045746475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STN1	NM_024928.5	c.451A>T	p.Thr151Ser	missense_variant	Exon 5 of 10	ENST00000224950.8	NP_079204.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STN1	ENST00000224950.8	c.451A>T	p.Thr151Ser	missense_variant	Exon 5 of 10	1	NM_024928.5	ENSP00000224950.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251018 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000547 AC: 8 AN: 1461614 Hom.: 0 Cov.: 42 AF XY: 0.00000413 AC XY: 3 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 151 of the STN1 protein (p.Thr151Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with STN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1505571). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt STN1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.19
DANN	Benign	0.84
DEOGEN2	Benign	0.0051	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.024	.;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		-1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.023
Sift	Benign	0.38	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.012	B;B
Vest4		0.14
MutPred		0.19		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.067
MPC		0.12
ClinPred		0.045	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.065
gMVP		0.30
Mutation Taster		=92/8	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: rs2487999; hg19: chr10-105659826;