17-40628808-G-C

Position:

• chr17-40628808-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003079.5(SMARCE1):​c.1213C>G​(p.Pro405Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,840 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P405L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.38

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09897691).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCE1	NM_003079.5	c.1213C>G	p.Pro405Ala	missense_variant	11/11	ENST00000348513.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCE1	ENST00000348513.12	c.1213C>G	p.Pro405Ala	missense_variant	11/11	1	NM_003079.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250976 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460840 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 726766

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial meningioma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 11, 2023	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 405 of the SMARCE1 protein (p.Pro405Ala). This variant is present in population databases (rs767835921, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SMARCE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 654067). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2023

The p.P405A variant (also known as c.1213C>G), located in coding exon 10 of the SMARCE1 gene, results from a C to G substitution at nucleotide position 1213. The proline at codon 405 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCE1 are known to cause neurodevelopmental disorders; however, such associations with increased risk of meningiomas are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Smith JM et al. Nat Genet. 2013 Mar;45(3):295-8). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with an increased risk of meningiomas is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.12	T;.;.;.;T;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0036
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.099	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.;D;.
REVEL	Benign	0.079
Sift	Benign	0.19	T;.;.;.;.;.;T;.
Sift4G	Benign	0.19	T;.;.;.;.;.;T;T
Polyphen		0.0	B;.;.;.;B;.;.;.
Vest4		0.10
MutPred		0.20		Gain of helix (P = 0.027);.;.;.;Gain of helix (P = 0.027);.;.;.;
MVP		0.18
MPC		0.56
ClinPred		0.18	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.021

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs767835921; hg19: chr17-38785060;