Variant 3-136338266-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005862.3(STAG1):c.3765G>A(p.Met1255Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,270 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: 0.0000014 ( 0 hom. )

Consequence

STAG1
NM_005862.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.22

Variant links:

Genes affected

STAG1 (HGNC:11354): (STAG1 cohesin complex component) This gene is a member of the SCC3 family and is expressed in the nucleus. It encodes a component of cohesin, a multisubunit protein complex that provides sister chromatid cohesion along the length of a chromosome from DNA replication through prophase and prometaphase, after which it is dissociated in preparation for segregation during anaphase. [provided by RefSeq, Jul 2008]

STAG1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the STAG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 4.4429 (above the threshold of 3.09). Trascript score misZ: 4.1606 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, intellectual disability, autosomal dominant 47.

BP4

Computational evidence support a benign effect (MetaRNN=0.20303285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAG1	NM_005862.3 link	c.3765G>A	p.Met1255Ile	missense_variant	34/34	ENST00000383202.7	NP_005853.2	Q8WVM7-1Q4LE48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAG1	ENST00000383202.7 link	c.3765G>A	p.Met1255Ile	missense_variant	34/34	1	NM_005862.3	ENSP00000372689.2		Q8WVM7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2024

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1255 of the STAG1 protein (p.Met1255Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAG1-related conditions. 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 STAG1 protein function with a negative predictive value of 95%. 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

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.021

T;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.0091

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.19

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.059

T;T;D

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.55

MutPred

0.15

Loss of glycosylation at S1251 (P = 0.1773);.;.;

MVP

0.45

MPC

0.88

ClinPred

0.93

GERP RS

5.8

Varity_R

0.35

gMVP

0.39

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over