19-10991262-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP3BP6

The NM_001387283.1(SMARCA4):c.1358C>T(p.Thr453Ile) 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. 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. T453A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.88

Publications

0 publications found

Variant links:

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

SMARCA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001387283.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

BP6

Variant 19-10991262-C-T is Benign according to our data. Variant chr19-10991262-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374051.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 9 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 8 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.1358C>T	p.Thr453Ile	missense_variant	Exon 9 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.770C>T	p.Thr257Ile	missense_variant	Exon 5 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.2C>T	p.Thr1Ile	missense_variant	Exon 1 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.86C>T	p.Thr29Ile	missense_variant	Exon 1 of 27			ENSP00000493615.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Oct 27, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3,BS2. -

Ventricular septal defect;C0038379:Strabismus;C0424731:Single transverse palmar crease;C0557874:Global developmental delay;C1306710:Facial asymmetry

Benign:1

Jan 23, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely benign

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

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.4

M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.6

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D

Sift4G

Uncertain

0.031

D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D

Vest4

0.73

MutPred

0.41

Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);Loss of phosphorylation at T453 (P = 0.0238);

MVP

0.66

MPC

2.6

ClinPred

0.87

GERP RS

4.9

PromoterAI

0.045

Neutral

(source)

Varity_R

0.78

gMVP

0.99

Mutation Taster

=16/84

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over