19-10986523-CGGCCCTGGCCCTGGCCCT-CGGCCCTGGCCCTGGCCCTGGCCCT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS1

The NM_003072.5(SMARCA4):c.708_713dupTGGCCC(p.Pro238_Gly239insGlyPro) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000551 in 1,543,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P238P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 6.83

Publications

1 publications found

Variant links:

COSMIC-nc: COSV60809415

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: Illumina, Orphanet, ClinGen
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
otosclerosis
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
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: Unknown Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003072.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003072.5

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000539 (75/1391208) while in subpopulation AFR AF = 0.000285 (9/31580). AF 95% confidence interval is 0.000148. There are 0 homozygotes in GnomAdExome4. There are 43 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003072.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCA4	NM_001387283.1	MANE Plus Clinical	c.708_713dupTGGCCC	p.Pro238_Gly239insGlyPro	disruptive_inframe_insertion	Exon 4 of 36	NP_001374212.1	Q9HBD4
SMARCA4	NM_003072.5	MANE Select	c.708_713dupTGGCCC	p.Pro238_Gly239insGlyPro	disruptive_inframe_insertion	Exon 4 of 35	NP_003063.2
SMARCA4	NM_001128849.3		c.708_713dupTGGCCC	p.Pro238_Gly239insGlyPro	disruptive_inframe_insertion	Exon 4 of 36	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.708_713dupTGGCCC	p.Pro238_Gly239insGlyPro	disruptive_inframe_insertion	Exon 4 of 36	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.708_713dupTGGCCC	p.Pro238_Gly239insGlyPro	disruptive_inframe_insertion	Exon 4 of 35	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1		c.708_713dupTGGCCC	p.Pro238_Gly239insGlyPro	disruptive_inframe_insertion	Exon 4 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000789

AC:

AN:

139340

AF XY:

0.0000397

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000163

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000924

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000765

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000539

AC:

AN:

1391208

Hom.:

Cov.:

AF XY:

0.0000626

AC XY:

AN XY:

686496

show subpopulations

African (AFR)

AF:

0.000285

AC:

AN:

31580

American (AMR)

AF:

0.000196

AC:

AN:

35666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25116

East Asian (EAS)

AF:

0.00

AC:

AN:

35728

South Asian (SAS)

AF:

0.0000758

AC:

AN:

79182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41640

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

1078664

Other (OTH)

AF:

0.0000690

AC:

AN:

57938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000657

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000868

Hom.:

Bravo

AF:

0.0000491

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Rhabdoid tumor predisposition syndrome 2 (1)

SMARCA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.8

Mutation Taster

=80/20

polymorphism

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over