NM_001387283.1:c.2438+4A>C

Variant names:

• chr19-11013116-A-C
• rs771818596
• NM_001387283.1:c.2438+4A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001387283.1(SMARCA4):​c.2438+4A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000031 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 splice_region, intron
• Scores: Splicing: ADA: 0.9927
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.16

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]

ENSG00000266936 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2438+4A>C		splice_region_variant, intron_variant	Intron 17 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2438+4A>C		splice_region_variant, intron_variant	Intron 16 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2438+4A>C		splice_region_variant, intron_variant	Intron 17 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1850+4A>C		splice_region_variant, intron_variant	Intron 13 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1082+4A>C		splice_region_variant, intron_variant	Intron 9 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1163+4A>C		splice_region_variant, intron_variant	Intron 9 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.923+4A>C		splice_region_variant, intron_variant	Intron 8 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.791+4A>C		splice_region_variant, intron_variant	Intron 7 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250424 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2438+4A>C intronic variant results from an A to C substitution 4 nucleotides after coding exon 15 in the SMARCA4 gene. This nucleotide position is well conserved in available vertebrate species. This variant has been detected in multiple individuals with no reported features of Coffin-Sirus syndrome-associated disease (Ambry internal data). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Sep 09, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.020		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: rs771818596; hg19: chr19-11123792;