17-40637511-T-C

Variant names:

• chr17-40637511-T-C
• rs387906857
• NM_003079.5:c.218A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003079.5(SMARCE1):​c.218A>G​(p.Tyr73Cys) 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. Y73S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.94
• Publications: 14 publications found

Genes affected

SMARCE1 (HGNC:11109): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1) The protein encoded by this gene is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. The encoded protein, either alone or when in the SWI/SNF complex, can bind to 4-way junction DNA, which is thought to mimic the topology of DNA as it enters or exits the nucleosome. The protein contains a DNA-binding HMG domain, but disruption of this domain does not abolish the DNA-binding or nucleosome-displacement activities of the SWI/SNF complex. Unlike most of the SWI/SNF complex proteins, this protein has no yeast counterpart. [provided by RefSeq, Jul 2008]

SMARCE1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• familial meningioma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen, Ambry Genetics
• Coffin-Siris syndrome 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000264058 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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, 6 uncertain in NM_003079.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40637511-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225845.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 17-40637511-T-C is Pathogenic according to our data. Variant chr17-40637511-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 30316.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003079.5. 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
	SMARCE1	NM_003079.5	MANE Select	c.218A>G	p.Tyr73Cys	missense	Exon 5 of 11	NP_003070.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCE1	ENST00000348513.12	TSL:1 MANE Select	c.218A>G	p.Tyr73Cys	missense	Exon 5 of 11	ENSP00000323967.6	Q969G3-1
	SMARCE1	ENST00000578044.6	TSL:1	c.8A>G	p.Tyr3Cys	missense	Exon 2 of 8	ENSP00000464511.1	Q969G3-3
	SMARCE1	ENST00000377808.9	TSL:1	c.113A>G	p.Tyr38Cys	missense	Exon 4 of 11	ENSP00000367039.4	Q969G3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Coffin-Siris syndrome 5 (1)
1	-	-	Familial meningioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.80		Gain of catalytic residue at M71 (P = 7e-04)
MVP		0.96
MPC		3.3
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=1/99	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: rs387906857; hg19: chr17-38793763; COSMIC: COSV62176582; COSMIC: COSV62176582;