NM_001387283.1:c.1257G>C

Variant names:

• chr19-10991161-G-C
• rs878854199
• NM_001387283.1:c.1257G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387283.1(SMARCA4):​c.1257G>C​(p.Glu419Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E419Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.694
• Publications: 0 publications found

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12781104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1257G>C	p.Glu419Asp	missense_variant	Exon 9 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1257G>C	p.Glu419Asp	missense_variant	Exon 9 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.669G>C	p.Glu223Asp	missense_variant	Exon 5 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.-100G>C		upstream_gene_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.-16G>C		upstream_gene_variant				ENSP00000493615.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E419D variant (also known as c.1257G>C), located in coding exon 7 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 1257. The glutamic acid at codon 419 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PhyloP100		0.69
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.9	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.17	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.15	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.22	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.51
MutPred		0.25		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.54
MPC		1.2
ClinPred		0.36	T
GERP RS		0.43
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.47
gMVP		0.98
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs878854199; hg19: chr19-11101837;