17-40637511-T-G

Variant names:

• chr17-40637511-T-G
• rs387906857
• NM_003079.5:c.218A>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003079.5(SMARCE1):​c.218A>C​(p.Tyr73Ser) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y73C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.94

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 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40637511-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 17-40637511-T-G is Pathogenic according to our data. Variant chr17-40637511-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 225845.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-40637511-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCE1	NM_003079.5	c.218A>C	p.Tyr73Ser	missense_variant	Exon 5 of 11	ENST00000348513.12	NP_003070.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCE1	ENST00000348513.12	c.218A>C	p.Tyr73Ser	missense_variant	Exon 5 of 11	1	NM_003079.5	ENSP00000323967.6
ENSG00000264058	ENST00000476049.1	n.*599-998A>C		intron_variant	Intron 7 of 12	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Coffin-Siris syndrome 5 Pathogenic:1

Dec 20, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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	32
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;H;.;.;.;.;H;.;H;.;.;.;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-8.8	D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.99
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		0.96
MutPred		0.83		Gain of disorder (P = 0.0081);.;.;.;Gain of disorder (P = 0.0081);.;.;.;.;Gain of disorder (P = 0.0081);.;Gain of disorder (P = 0.0081);.;.;.;Gain of disorder (P = 0.0081);.;Gain of disorder (P = 0.0081);.;.;.;Gain of disorder (P = 0.0081);
MVP		0.97
MPC		3.2
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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: rs387906857; hg19: chr17-38793763;