17-40636453-C-G

Position:

• chr17-40636453-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003079.5(SMARCE1):​c.311G>C​(p.Trp104Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83

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]

ENSG00000264058 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a DNA_binding_region HMG box (size 68) in uniprot entity SMCE1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003079.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-40636453-C-G is Pathogenic according to our data. Variant chr17-40636453-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424096.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCE1	NM_003079.5	c.311G>C	p.Trp104Ser	missense_variant	6/11	ENST00000348513.12	NP_003070.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCE1	ENST00000348513.12	c.311G>C	p.Trp104Ser	missense_variant	6/11	1	NM_003079.5	ENSP00000323967.6
ENSG00000264058	ENST00000476049.1	n.*659G>C		non_coding_transcript_exon_variant	8/13	5		ENSP00000463483.1
ENSG00000264058	ENST00000476049.1	n.*659G>C		3_prime_UTR_variant	8/13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2017

The W104S variant in the SMARCE1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The W104S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W104S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The W104S variant is a strong candidate for a pathogenic variant, consistent with the clinical features reported in this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;H;.;.;.;.;H;.;H;.;.;.;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-14	D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;D;.;D;D;.;.;.;D;D;.;.;.;.;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.89		Gain of disorder (P = 0.0022);.;.;.;Gain of disorder (P = 0.0022);.;.;.;.;Gain of disorder (P = 0.0022);.;Gain of disorder (P = 0.0022);.;.;.;Gain of disorder (P = 0.0022);.;Gain of disorder (P = 0.0022);.;.;.;Gain of disorder (P = 0.0022);
MVP		0.98
MPC		3.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		1.0

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: rs397509407; hg19: chr17-38792705;