NM_001387283.1:c.3954C>T

Variant names:

• chr19-11034916-C-T
• rs1555785323
• NM_001387283.1:c.3954C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001387283.1(SMARCA4):​c.3954C>T​(p.Arg1318Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,409,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1318R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.388
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 19-11034916-C-T is Benign according to our data. Variant chr19-11034916-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 537797.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.

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.3954C>T	p.Arg1318Arg	splice_region synonymous	Exon 29 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.3954C>T	p.Arg1318Arg	splice_region synonymous	Exon 29 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.3954C>T	p.Arg1318Arg	splice_region synonymous	Exon 29 of 36	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.3954C>T	p.Arg1318Arg	splice_region synonymous	Exon 29 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.3954C>T	p.Arg1318Arg	splice_region synonymous	Exon 29 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.3855C>T	p.Arg1285Arg	splice_region synonymous	Exon 28 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000568 AC: 8 AN: 1409406 Hom.: 0 Cov.: 32 AF XY: 0.00000574 AC XY: 4 AN XY: 696474

African (AFR) AF: 0.00 AC: 0 AN: 32224

American (AMR) AF: 0.00 AC: 0 AN: 36994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 36932

South Asian (SAS) AF: 0.00 AC: 0 AN: 80188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4388

European-Non Finnish (NFE) AF: 0.00000644 AC: 7 AN: 1086340

Other (OTH) AF: 0.0000171 AC: 1 AN: 58406

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rhabdoid tumor predisposition syndrome 2 Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Mar 21, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		0.39
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555785323; hg19: chr19-11145592;