3-136443400-T-A

Variant names:

• chr3-136443400-T-A
• rs1553722309
• NM_005862.3:c.1433A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H478P) has been classified 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 47

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-136443400-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 437897.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 VariationId is 3629946.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005862.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAG1	NM_005862.3	MANE Select	c.1433A>T	p.His478Leu	missense	Exon 15 of 34	NP_005853.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAG1	ENST00000383202.7	TSL:1 MANE Select	c.1433A>T	p.His478Leu	missense	Exon 15 of 34	ENSP00000372689.2
	STAG1	ENST00000236698.9	TSL:1	c.1433A>T	p.His478Leu	missense	Exon 15 of 33	ENSP00000236698.5
	STAG1	ENST00000483235.5	TSL:1	n.*1525A>T		non_coding_transcript_exon	Exon 18 of 36	ENSP00000419093.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 47 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.96	D
Vest4		0.81
MutPred		0.65		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
Mutation Taster		=7/93	disease causing

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: rs1553722309; hg19: chr3-136162242;