Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001387283.1(SMARCA4):c.1413G>A(p.Lys471Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,597,060 control chromosomes in the GnomAD database, including 1,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 126 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1284 hom. )

Consequence

SMARCA4
NM_001387283.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.27

Publications

15 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 19-10991317-G-A is Benign according to our data. Variant chr19-10991317-G-A is described in ClinVar as Benign. ClinVar VariationId is 126356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0329 (5015/152374) while in subpopulation NFE AF = 0.041 (2787/68040). AF 95% confidence interval is 0.0397. There are 126 homozygotes in GnomAd4. There are 2252 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 126 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA4	NM_001387283.1	MANE Plus Clinical	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 36	NP_001374212.1
SMARCA4	NM_003072.5	MANE Select	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 35	NP_003063.2
SMARCA4	NM_001128849.3		c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 36	NP_001122321.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 36	ENSP00000495368.1
SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 35	ENSP00000343896.4
SMARCA4	ENST00000643549.1		c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

5006

AN:

152256

Hom.:

125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0349

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0410

Gnomad OTH

AF:

0.0387

GnomAD2 exomes

AF:

0.0257

AC:

5535

AN:

214992

AF XY:

0.0256

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.0174

Gnomad ASJ exome

AF:

0.0203

Gnomad EAS exome

AF:

0.000126

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0401

Gnomad OTH exome

AF:

0.0258

GnomAD4 exome

AF:

0.0380

AC:

54911

AN:

1444686

Hom.:

1284

Cov.:

AF XY:

0.0370

AC XY:

26565

AN XY:

717066

show subpopulations

African (AFR)

AF:

0.0346

AC:

1148

AN:

33216

American (AMR)

AF:

0.0185

AC:

768

AN:

41618

Ashkenazi Jewish (ASJ)

AF:

0.0195

AC:

503

AN:

25816

East Asian (EAS)

AF:

0.0000770

AC:

AN:

38940

South Asian (SAS)

AF:

0.00459

AC:

385

AN:

83920

European-Finnish (FIN)

AF:

0.0179

AC:

923

AN:

51674

Middle Eastern (MID)

AF:

0.0213

AC:

115

AN:

5400

European-Non Finnish (NFE)

AF:

0.0442

AC:

48855

AN:

1104348

Other (OTH)

AF:

0.0370

AC:

2211

AN:

59754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2889

5778

8668

11557

14446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1856

3712

5568

7424

9280

<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:

0.0329

AC:

5015

AN:

152374

Hom.:

126

Cov.:

AF XY:

0.0302

AC XY:

2252

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0350

AC:

1457

AN:

41592

American (AMR)

AF:

0.0267

AC:

409

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00248

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0165

AC:

175

AN:

10632

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0410

AC:

2787

AN:

68040

Other (OTH)

AF:

0.0383

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

260

520

781

1041

1301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0368

Hom.:

176

Bravo

AF:

0.0340

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Coffin-Siris syndrome (1)

Hereditary cancer-predisposing syndrome (1)

Intellectual disability, autosomal dominant 16 (1)

Rhabdoid tumor predisposition syndrome 2 (1)

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.1

(source)

DANN

Benign

0.61

PhyloP100

2.3

PromoterAI

0.050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over