17-40628808-G-C

Variant names:

• chr17-40628808-G-C
• rs767835921
• NM_003079.5:c.1213C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P405T) 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.38
• Publications: 0 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09897691).
• BP6: Variant 17-40628808-G-C is Benign according to our data. Variant chr17-40628808-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 654067.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

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.1213C>G	p.Pro405Ala	missense	Exon 11 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.1213C>G	p.Pro405Ala	missense	Exon 11 of 11	ENSP00000323967.6	Q969G3-1
	SMARCE1	ENST00000578044.6	TSL:1	c.1003C>G	p.Pro335Ala	missense	Exon 8 of 8	ENSP00000464511.1	Q969G3-3
	SMARCE1	ENST00000377808.9	TSL:1	c.*200C>G		3_prime_UTR	Exon 11 of 11	ENSP00000367039.4	Q969G3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250976 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111220

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Familial meningioma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0036
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N
PhyloP100		3.4
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.079
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.20		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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs767835921; hg19: chr17-38785060;