chr3-136443400-T-A

Variant names:

• chr3-136443400-T-A
• NM_005862.3:c.1433A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_005862.3(STAG1):​c.1433A>T​(p.His478Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAG1 NM_005862.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 3-136443400-T-A is Pathogenic according to our data. Variant chr3-136443400-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3629946.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAG1	NM_005862.3	c.1433A>T	p.His478Leu	missense_variant	Exon 15 of 34	ENST00000383202.7	NP_005853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAG1	ENST00000383202.7	c.1433A>T	p.His478Leu	missense_variant	Exon 15 of 34	1	NM_005862.3	ENSP00000372689.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 47 Pathogenic:1

Nov 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STAG1 c.1433A>T (p.His478Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1433A>T was seen internally de novo in a patient affected with Intellectual disability. A different variant at this position p.H478P has also been reported in a patient affected with Intellectual disability and was reported as de novo (PMID: 28119487). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.96	D;.;.
Vest4		0.81
MutPred		0.65		Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);.;
MVP		0.54
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.61

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.

Other links and lift over

hg19: chr3-136162242;