10-103900068-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024928.5(STN1):​c.451A>G​(p.Thr151Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 1,613,648 control chromosomes in the GnomAD database, including 657,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T151S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.85 (55440 hom., cov: 32)
  • Exomes 𝑓: 0.91 (602320 hom.)
• Consequence: STN1 NM_024928.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Ambry Genetics, Genomics England PanelApp, PanelApp Australia, G2P
• Coats plus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289744 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8094437E-7).
• BP6: Variant 10-103900068-T-C is Benign according to our data. Variant chr10-103900068-T-C is described in ClinVar as Benign. ClinVar VariationId is 1169388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024928.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STN1	NM_024928.5	MANE Select	c.451A>G	p.Thr151Ala	missense	Exon 5 of 10	NP_079204.2	Q9H668

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STN1	ENST00000224950.8	TSL:1 MANE Select	c.451A>G	p.Thr151Ala	missense	Exon 5 of 10	ENSP00000224950.3	Q9H668
	STN1	ENST00000698305.1		c.451A>G	p.Thr151Ala	missense	Exon 5 of 10	ENSP00000513665.1	A0A8V8TM56
	STN1	ENST00000369764.2	TSL:2	c.451A>G	p.Thr151Ala	missense	Exon 4 of 9	ENSP00000358779.1	Q9H668

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128746 AN: 152086 Hom.: 55409 Cov.: 32

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.951

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.912

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.868

GnomAD2 exomes AF: 0.912 AC: 228833 AN: 251018 AF XY: 0.917

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.946

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.918

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.907 AC: 1325010 AN: 1461444 Hom.: 602320 Cov.: 42 AF XY: 0.909 AC XY: 660926 AN XY: 727024

African (AFR) AF: 0.660 AC: 22085 AN: 33460

American (AMR) AF: 0.942 AC: 42100 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 23825 AN: 26124

East Asian (EAS) AF: 1.00 AC: 39695 AN: 39698

South Asian (SAS) AF: 0.981 AC: 84566 AN: 86230

European-Finnish (FIN) AF: 0.920 AC: 49109 AN: 53408

Middle Eastern (MID) AF: 0.903 AC: 5211 AN: 5768

European-Non Finnish (NFE) AF: 0.903 AC: 1003669 AN: 1111678

Other (OTH) AF: 0.907 AC: 54750 AN: 60374

GnomAD4 genome AF: 0.846 AC: 128823 AN: 152204 Hom.: 55440 Cov.: 32 AF XY: 0.851 AC XY: 63360 AN XY: 74414

African (AFR) AF: 0.674 AC: 27936 AN: 41460

American (AMR) AF: 0.919 AC: 14058 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3156 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5175 AN: 5176

South Asian (SAS) AF: 0.982 AC: 4741 AN: 4830

European-Finnish (FIN) AF: 0.912 AC: 9678 AN: 10616

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 61109 AN: 68030

Other (OTH) AF: 0.870 AC: 1839 AN: 2114

Alfa AF: 0.885 Hom.: 221835

Bravo AF: 0.839

TwinsUK AF: 0.901 AC: 3342

ALSPAC AF: 0.900 AC: 3470

ESP6500AA AF: 0.678 AC: 2987

ESP6500EA AF: 0.897 AC: 7714

ExAC AF: 0.907 AC: 110134

Asia WGS AF: 0.965 AC: 3356 AN: 3478

EpiCase AF: 0.896

EpiControl AF: 0.901

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cerebroretinal microangiopathy with calcifications and cysts 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.17
DANN	Benign	0.71
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.013	T
MetaRNN	Benign	6.8e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.65	N
PhyloP100		-1.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.031
Sift	Benign	0.67	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.13
ClinPred		0.0015	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.071
gMVP		0.34
Mutation Taster		=93/7	polymorphism (auto)

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; COSMIC: COSV108081682;