chr19-11030724-C-T

Variant names:

• chr19-11030724-C-T
• rs760118048
• NM_001387283.1:c.3383-6C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001387283.1(SMARCA4):​c.3383-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,610,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 splice_region, intron
• Scores: Splicing: ADA: 0.00002610
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.34
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11030724-C-T is Benign according to our data. Variant chr19-11030724-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 470347.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000046 (7/152182) while in subpopulation AFR AF = 0.000145 (6/41438). AF 95% confidence interval is 0.0000628. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3383-6C>T		splice_region_variant, intron_variant	Intron 25 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3383-6C>T		splice_region_variant, intron_variant	Intron 24 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3383-6C>T		splice_region_variant, intron_variant	Intron 25 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2795-6C>T		splice_region_variant, intron_variant	Intron 21 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2027-6C>T		splice_region_variant, intron_variant	Intron 17 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2108-6C>T		splice_region_variant, intron_variant	Intron 17 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1868-6C>T		splice_region_variant, intron_variant	Intron 16 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1736-6C>T		splice_region_variant, intron_variant	Intron 15 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 243122 AF XY: 0.0000151

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000917

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458142 Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5 AN XY: 725116

African (AFR) AF: 0.0000898 AC: 3 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110680

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.000145 AC: 6 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.75
DANN	Benign	0.67
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
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: rs760118048; hg19: chr19-11141400;