19-11034206-C-T

Variant names:

• chr19-11034206-C-T
• rs759241380
• NM_001387283.1:c.3951+6C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003072.5(SMARCA4):​c.3951+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 0.0000048 in 1,458,406 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004829
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.511

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-11034206-C-T is Benign according to our data. Variant chr19-11034206-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 470375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3951+6C>T		splice_region_variant, intron_variant	Intron 28 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3951+6C>T		splice_region_variant, intron_variant	Intron 28 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3951+6C>T		splice_region_variant, intron_variant	Intron 28 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3951+6C>T		splice_region_variant, intron_variant	Intron 28 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3852+6C>T		splice_region_variant, intron_variant	Intron 27 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3852+6C>T		splice_region_variant, intron_variant	Intron 28 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3852+6C>T		splice_region_variant, intron_variant	Intron 27 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3852+6C>T		splice_region_variant, intron_variant	Intron 27 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3852+6C>T		splice_region_variant, intron_variant	Intron 28 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3363+6C>T		splice_region_variant, intron_variant	Intron 25 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2595+6C>T		splice_region_variant, intron_variant	Intron 21 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2577+6C>T		splice_region_variant, intron_variant	Intron 20 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2436+6C>T		splice_region_variant, intron_variant	Intron 20 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2304+6C>T		splice_region_variant, intron_variant	Intron 19 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.108+6C>T		splice_region_variant, intron_variant	Intron 2 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250658 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458406 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 28, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMARCA4-related disorder Benign:1

May 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.3
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
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

Publications

LitVar

Other links and lift over

dbSNP: rs759241380; hg19: chr19-11144882; COSMIC: COSV60799402; COSMIC: COSV60799402;