rs199814381

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001387283.1(SMARCA4):c.1419+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,584,582 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 splice_region, intron

Scores

Splicing: ADA: 0.3936

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.994

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 19-10991328-G-A is Benign according to our data. Variant chr19-10991328-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 480584.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000656 (10/152378) while in subpopulation AFR AF = 0.00024 (10/41596). AF 95% confidence interval is 0.00013. There are 1 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1419+5G>A		splice_region_variant, intron_variant	Intron 8 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1419+5G>A		splice_region_variant, intron_variant	Intron 8 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 8 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 8 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 8 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 9 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 8 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 8 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.1419+5G>A	splice_region_variant, intron_variant	Intron 9 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.831+5G>A	splice_region_variant, intron_variant	Intron 5 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.63+5G>A	splice_region_variant, intron_variant	Intron 1 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.147+5G>A	splice_region_variant, intron_variant	Intron 1 of 26			ENSP00000493615.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000309

AC:

AN:

193872

AF XY:

0.0000479

show subpopulations

Gnomad AFR exome

AF:

0.000172

Gnomad AMR exome

AF:

0.000107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000768

AC:

AN:

1432204

Hom.:

Cov.:

AF XY:

0.00000845

AC XY:

AN XY:

709742

show subpopulations

African (AFR)

AF:

0.0000607

AC:

AN:

32944

American (AMR)

AF:

0.0000758

AC:

AN:

39584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25612

East Asian (EAS)

AF:

0.00

AC:

AN:

38176

South Asian (SAS)

AF:

0.0000726

AC:

AN:

82594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5156

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098084

Other (OTH)

AF:

0.00

AC:

AN:

59292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.0000656

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74526

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000661

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0002 (4/20368 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on SMARCA4 mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.

Intellectual disability, autosomal dominant 16

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Rhabdoid tumor predisposition syndrome 2

Benign:1

Jan 08, 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

Oct 07, 2019

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.

SMARCA4-related disorder

Benign:1

Aug 06, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

0.99

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.39

dbscSNV1_RF

Benign

0.39

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over