chr19-11012950-T-C

Variant names:

• chr19-11012950-T-C
• rs878854206
• NM_001387283.1:c.2276T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001387283.1(SMARCA4):​c.2276T>C​(p.Ile759Thr) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I759M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense, splice_region
• Scores: Splicing: ADA: 0.1707
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• 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

ENSG00000266936 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001387283.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 17 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 16 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2276T>C	p.Ile759Thr	missense_variant, splice_region_variant	Exon 17 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1688T>C	p.Ile563Thr	missense_variant, splice_region_variant	Exon 13 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.920T>C	p.Ile307Thr	missense_variant, splice_region_variant	Exon 9 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1001T>C	p.Ile334Thr	missense_variant, splice_region_variant	Exon 9 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.761T>C	p.Ile254Thr	missense_variant, splice_region_variant	Exon 8 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.629T>C	p.Ile210Thr	missense_variant, splice_region_variant	Exon 7 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 759 of the SMARCA4 protein (p.Ile759Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 238399). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.024	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.050	T;.;.;.;.;.;.;.;.;.;T;.;D;T;T;D;D;D;.;.;.;.
Polyphen		0.21	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.85
MutPred		0.65		Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);.;Loss of stability (P = 0.0107);.;.;.;.;
MVP		0.98
MPC		2.3
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.70
gMVP		0.90
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.17
dbscSNV1_RF	Benign	0.37
SpliceAI score (max)		0.020		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: rs878854206; hg19: chr19-11123626;