rs1555605795

chr17-40636488-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_003079.5(SMARCE1):c.276G>C(p.Lys92Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K92Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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, 7 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 chr17-40636490-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1335269.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 17-40636488-C-G is Pathogenic according to our data. Variant chr17-40636488-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40636488-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCE1	NM_003079.5	c.276G>C	p.Lys92Asn	missense_variant	6/11	ENST00000348513.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCE1	ENST00000348513.12	c.276G>C	p.Lys92Asn	missense_variant	6/11	1	NM_003079.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Coffin-Siris syndrome 5 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Sep 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;D;.;D
Eigen	Benign	0.053
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.4	M;.;.;.;M;.;.;.;.;M;.;M;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;N;.;.;.;.;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.013	D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.045	D;.;.;.;.;D;.;T;T;.;.;.;D;D;.;.;.;.;.;.;.;D
Polyphen		0.066	B;.;.;.;.;.;.;.;.;B;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.49		Loss of ubiquitination at K92 (P = 0.0148);.;.;.;Loss of ubiquitination at K92 (P = 0.0148);.;.;.;.;Loss of ubiquitination at K92 (P = 0.0148);.;Loss of ubiquitination at K92 (P = 0.0148);.;.;.;Loss of ubiquitination at K92 (P = 0.0148);.;Loss of ubiquitination at K92 (P = 0.0148);.;.;.;Loss of ubiquitination at K92 (P = 0.0148);
MVP		0.89
MPC		2.8
ClinPred		0.97	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs1555605795; hg19: chr17-38792740;