19-11021761-C-T

Variant names:

• chr19-11021761-C-T
• rs281875227
• NM_001387283.1:c.2653C>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003072.5(SMARCA4):​c.2653C>T​(p.Arg885Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R885H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 165) in uniprot entity SMCA4_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003072.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11021762-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 19-11021761-C-T is Pathogenic according to our data. Variant chr19-11021761-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11021761-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2653C>T	p.Arg885Cys	missense_variant	Exon 20 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2653C>T	p.Arg885Cys	missense_variant	Exon 19 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2653C>T	p.Arg885Cys	missense_variant	Exon 20 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2065C>T	p.Arg689Cys	missense_variant	Exon 16 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1297C>T	p.Arg433Cys	missense_variant	Exon 12 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1378C>T	p.Arg460Cys	missense_variant	Exon 12 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1138C>T	p.Arg380Cys	missense_variant	Exon 11 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1006C>T	p.Arg336Cys	missense_variant	Exon 10 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Pathogenic:3

Sep 07, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

Mar 23, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R885C variant in the SMARCA4 gene has been reported previously in at least one individual with Coffin-Siris syndrome (Tsurusaki et al., 2012). The R885C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R885C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (R885H) has been reported in the Human Gene Mutation Database in association with Coffin-Siris Syndrome (Kosho et al., 2013; Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, we interpret R885C as a pathogenic variant. -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Mar 10, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.5	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.86
MutPred		0.92		Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);.;Loss of MoRF binding (P = 0.0028);.;.;.;.;
MVP		0.99
MPC		4.3
ClinPred		1.0	D
GERP RS		2.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.96
gMVP		0.97

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: rs281875227; hg19: chr19-11132437; COSMIC: COSV60785471;