22-23833655-C-T

Variant names:

• chr22-23833655-C-T
• rs1555881567
• NM_003073.5:c.1070C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003073.5(SMARCB1):​c.1070C>T​(p.Thr357Ile) 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. 13/22 in silico tools predict a damaging 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. T357R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.66
• Publications: 0 publications found

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schwannomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23833655-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 559897.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 22-23833655-C-T is Pathogenic according to our data. Variant chr22-23833655-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 580796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.1070C>T	p.Thr357Ile	missense_variant	Exon 8 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.1124C>T	p.Thr375Ile	missense_variant	Exon 8 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.1097C>T	p.Thr366Ile	missense_variant	Exon 8 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.1043C>T	p.Thr348Ile	missense_variant	Exon 8 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1070C>T	p.Thr357Ile	missense_variant	Exon 8 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with isoleucine at codon 357 of the SMARCB1 protein (p.Thr357Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Coffin-Siris syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dec 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.5	.;M;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.8	D;.;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Uncertain	0.0020	D;.;D;.
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.84
MutPred		0.72		.;.;Loss of disorder (P = 0.0376);.;
MVP		0.89
MPC		2.6
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.99
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs1555881567; hg19: chr22-24175842;