NM_001387283.1:c.4521-2104G>A

Variant names:

• chr19-11056151-G-A
• rs3786725
• NM_001387283.1:c.4521-2104G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001387283.1(SMARCA4):​c.4521-2104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,100 control chromosomes in the GnomAD database, including 4,943 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4942 hom., cov: 32)
  • Exomes 𝑓: 0.24 (1 hom.)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 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.4521-2104G>A		intron	N/A	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.4425-2104G>A		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.4521-2104G>A		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.4521-2104G>A		intron	N/A	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4425-2104G>A		intron	N/A	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.4431-2104G>A		intron	N/A	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37803 AN: 151940 Hom.: 4948 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.248

GnomAD4 exome AF: 0.238 AC: 10 AN: 42 Hom.: 1 AF XY: 0.321 AC XY: 9 AN XY: 28

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 2 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 3 AN: 24

Other (OTH) AF: 0.500 AC: 5 AN: 10

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000299060), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.249 AC: 37805 AN: 152058 Hom.: 4942 Cov.: 32 AF XY: 0.243 AC XY: 18065 AN XY: 74320

African (AFR) AF: 0.210 AC: 8710 AN: 41470

American (AMR) AF: 0.202 AC: 3091 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 885 AN: 3470

East Asian (EAS) AF: 0.102 AC: 525 AN: 5168

South Asian (SAS) AF: 0.240 AC: 1157 AN: 4822

European-Finnish (FIN) AF: 0.232 AC: 2452 AN: 10576

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20180 AN: 67966

Other (OTH) AF: 0.246 AC: 521 AN: 2114

Alfa AF: 0.282 Hom.: 8841

Bravo AF: 0.243

Asia WGS AF: 0.173 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.3
DANN	Benign	0.91
PhyloP100		0.40
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: rs3786725; hg19: chr19-11166827;