rs1221798183

Variant names:

• chr19-11035004-A-G
• rs1221798183
• NM_001387283.1:c.4042A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11035004-A-G
• chr19-11035004-A-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001387283.1(SMARCA4):​c.4042A>G​(p.Ile1348Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,459,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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. I1348S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.12
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09307155).
• BP6: Variant 19-11035004-A-G is Benign according to our data. Variant chr19-11035004-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470379.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4042A>G	p.Ile1348Val	missense_variant	Exon 29 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4042A>G	p.Ile1348Val	missense_variant	Exon 29 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4042A>G	p.Ile1348Val	missense_variant	Exon 29 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4042A>G	p.Ile1348Val	missense_variant	Exon 29 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3943A>G	p.Ile1315Val	missense_variant	Exon 28 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3943A>G	p.Ile1315Val	missense_variant	Exon 29 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3943A>G	p.Ile1315Val	missense_variant	Exon 28 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3943A>G	p.Ile1315Val	missense_variant	Exon 28 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3943A>G	p.Ile1315Val	missense_variant	Exon 29 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3454A>G	p.Ile1152Val	missense_variant	Exon 26 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2686A>G	p.Ile896Val	missense_variant	Exon 22 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2668A>G	p.Ile890Val	missense_variant	Exon 21 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2527A>G	p.Ile843Val	missense_variant	Exon 21 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2395A>G	p.Ile799Val	missense_variant	Exon 20 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.199A>G	p.Ile67Val	missense_variant	Exon 3 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 245032 AF XY: 0.00

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: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459398 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 725868

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 85930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111294

Other (OTH) AF: 0.0000166 AC: 1 AN: 60304

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Sep 27, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 470379). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1348 of the SMARCA4 protein (p.Ile1348Val). -

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 20, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.74
DEOGEN2	Benign	0.20	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-1.2	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.020	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.76	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.83	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.0020	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.20
MutPred		0.28		Loss of helix (P = 0.0104);.;Loss of helix (P = 0.0104);.;.;.;.;.;.;.;Loss of helix (P = 0.0104);.;.;.;.;.;.;Loss of helix (P = 0.0104);.;.;.;.;
MVP		0.50
MPC		1.4
ClinPred		0.091	T
GERP RS		4.6
La Branchor		0.55
PromoterAI		-0.0016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.083
gMVP		0.86
Mutation Taster		=79/21	polymorphism

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: rs1221798183; hg19: chr19-11145680;