rs11672232

chr19-10995924-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001387283.1(SMARCA4):c.1594-289C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 474,168 control chromosomes in the GnomAD database, including 27,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (7878 hom., cov: 32)
  • Exomes 𝑓: 0.34 (19540 hom.)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.356

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.463626E-4).
• BP6: Variant 19-10995924-C-T is Benign according to our data. Variant chr19-10995924-C-T is described in ClinVar as [Benign]. Clinvar id is 1237367.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-10995924-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1594-289C>T		intron_variant		ENST00000646693.2
SMARCA4	NM_003072.5	c.1594-289C>T		intron_variant		ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000344626.10	c.1594-289C>T		intron_variant		1	NM_003072.5	P4
SMARCA4	ENST00000646693.2	c.1594-289C>T		intron_variant			NM_001387283.1

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48260 AN: 151740 Hom.: 7860 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.316

GnomAD3 exomes AF: 0.306 AC: 19552 AN: 63824 Hom.: 3255 AF XY: 0.313 AC XY: 10114 AN XY: 32278

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.338 AC: 109085 AN: 322310 Hom.: 19540 Cov.: 0 AF XY: 0.346 AC XY: 60289 AN XY: 174114

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.361

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.318 AC: 48315 AN: 151858 Hom.: 7878 Cov.: 32 AF XY: 0.320 AC XY: 23731 AN XY: 74214

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.245

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.317

Alfa AF: 0.322 Hom.: 1063

Bravo AF: 0.304

TwinsUK AF: 0.359 AC: 1333

ALSPAC AF: 0.360 AC: 1388

ExAC AF: 0.169 AC: 6322

Asia WGS AF: 0.331 AC: 1153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.94
Dann	Benign	0.71
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00070	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.00035	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
Sift4G	Uncertain	0.0020	D
Vest4		0.14
ClinPred		0.0045	T
GERP RS		-5.0

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

LitVar

Other links and lift over

dbSNP: rs11672232; hg19: chr19-11106600; COSMIC: COSV60787333; COSMIC: COSV60787333;