chr19-10995924-C-T

Variant names:

• chr19-10995924-C-T
• rs11672232
• NM_001387283.1:c.1594-289C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.356
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1237367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.1594-289C>T		intron	N/A	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.1594-289C>T		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.1594-289C>T		intron	N/A	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.1594-289C>T		intron	N/A	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1594-289C>T		intron	N/A	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.1594-289C>T		intron	N/A	ENSP00000493975.1

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

GnomAD2 exomes AF: 0.306 AC: 19552 AN: 63824 AF XY: 0.313

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 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

African (AFR) AF: 0.277 AC: 2627 AN: 9496

American (AMR) AF: 0.203 AC: 3516 AN: 17282

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 3195 AN: 9580

East Asian (EAS) AF: 0.221 AC: 4056 AN: 18344

South Asian (SAS) AF: 0.429 AC: 19849 AN: 46250

European-Finnish (FIN) AF: 0.361 AC: 5500 AN: 15252

Middle Eastern (MID) AF: 0.375 AC: 1109 AN: 2960

European-Non Finnish (NFE) AF: 0.342 AC: 63382 AN: 185510

Other (OTH) AF: 0.332 AC: 5851 AN: 17636

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

African (AFR) AF: 0.282 AC: 11669 AN: 41410

American (AMR) AF: 0.236 AC: 3608 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1215 AN: 3468

East Asian (EAS) AF: 0.245 AC: 1264 AN: 5164

South Asian (SAS) AF: 0.412 AC: 1982 AN: 4808

European-Finnish (FIN) AF: 0.369 AC: 3893 AN: 10546

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23617 AN: 67886

Other (OTH) AF: 0.317 AC: 668 AN: 2106

Alfa AF: 0.322 Hom.: 1104

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
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
PhyloP100		-0.36
Sift4G	Uncertain	0.0020	D
Vest4		0.14
ClinPred		0.0045	T
GERP RS		-5.0
PromoterAI		-0.0060	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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