rs770680174

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_003072.5(SMARCA4):c.3608G>A(p.Arg1203His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 9.66

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a domain Helicase C-terminal (size 162) in uniprot entity SMCA4_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_003072.5

PM2

Very rare variant in population databases, with high coverage;

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, 0.969

PP5

Variant 19-11033351-G-A is Pathogenic according to our data. Variant chr19-11033351-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11033351-G-A is described in Lovd as [Pathogenic]. Variant chr19-11033351-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 27 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.3608G>A	p.Arg1203His	missense_variant	Exon 27 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.3020G>A	p.Arg1007His	missense_variant	Exon 23 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.2252G>A	p.Arg751His	missense_variant	Exon 19 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.2333G>A	p.Arg778His	missense_variant	Exon 19 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.2093G>A	p.Arg698His	missense_variant	Exon 18 of 27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.1961G>A	p.Arg654His	missense_variant	Exon 17 of 25			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 link	c.-137G>A		upstream_gene_variant		3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460922

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Oct 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25168959, 24090879, 25326635, 23929686, 24658002) -

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 16

Pathogenic:1Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 2-year-old male with global delays, agenesis of the corpus callosum, hypoplastic cerebellar vermis, cleft palate, Pierre-Robin, apnea, GERD, growth failure, ptosis, pyloric stenosis, dysmorphisms, microcephaly, hypoplastic 4th & 5th nails -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMARCA4-related BAFopathy

Pathogenic:1

Jun 10, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

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

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.3

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.99

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

Vest4

0.97

MutPred

0.82

Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);.;Loss of MoRF binding (P = 0.0464);.;.;.;

MVP

0.99

MPC

2.5

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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