19-11034916-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

The NM_001387283.1(SMARCA4):c.3954C>T(p.Arg1318Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,409,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1318R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 splice_region, synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.388

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.02).

BP6

Variant 19-11034916-C-T is Benign according to our data. Variant chr19-11034916-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 537797.

BP7

Synonymous conserved (PhyloP=0.388 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	Exon 29 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	Exon 29 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	Exon 29 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	Exon 29 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	Exon 28 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	Exon 29 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	Exon 28 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	Exon 28 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	Exon 29 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.3366C>T	p.Arg1122Arg	splice_region_variant, synonymous_variant	Exon 26 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.2598C>T	p.Arg866Arg	splice_region_variant, synonymous_variant	Exon 22 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.2580C>T	p.Arg860Arg	splice_region_variant, synonymous_variant	Exon 21 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.2439C>T	p.Arg813Arg	splice_region_variant, synonymous_variant	Exon 21 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.2307C>T	p.Arg769Arg	splice_region_variant, synonymous_variant	Exon 20 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.111C>T	p.Arg37Arg	splice_region_variant, synonymous_variant	Exon 3 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000568

AC:

AN:

1409406

Hom.:

Cov.:

AF XY:

0.00000574

AC XY:

AN XY:

696474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32224

American (AMR)

AF:

0.00

AC:

AN:

36994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25254

East Asian (EAS)

AF:

0.00

AC:

AN:

36932

South Asian (SAS)

AF:

0.00

AC:

AN:

80188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4388

European-Non Finnish (NFE)

AF:

0.00000644

AC:

AN:

1086340

Other (OTH)

AF:

0.0000171

AC:

AN:

58406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

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

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 21, 2018

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

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.39

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over