17-40628804-T-G

Position:

• chr17-40628804-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003079.5(SMARCE1):​c.1217A>C​(p.Glu406Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107123196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCE1	NM_003079.5	c.1217A>C	p.Glu406Ala	missense_variant	11/11	ENST00000348513.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCE1	ENST00000348513.12	c.1217A>C	p.Glu406Ala	missense_variant	11/11	1	NM_003079.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460954 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial meningioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 406 of the SMARCE1 protein (p.Glu406Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant has not been reported in the literature in individuals with SMARCE1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;.;.;T;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.;.;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;N;.
REVEL	Benign	0.098
Sift	Benign	0.059	T;.;.;.;.;.;T;.
Sift4G	Uncertain	0.052	T;.;.;.;.;.;T;T
Polyphen		0.0	B;.;.;.;B;.;.;.
Vest4		0.24
MutPred		0.069		Loss of helix (P = 0.0626);.;.;.;Loss of helix (P = 0.0626);.;.;.;
MVP		0.26
MPC		0.61
ClinPred		0.67	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.045

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2037060002; hg19: chr17-38785056;