rs377743250

Variant names:

• chr19-11021720-C-A
• rs377743250
• NM_001387283.1:c.2617-5C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11021720-C-A
• chr19-11021720-C-G
• chr19-11021720-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001387283.1(SMARCA4):​c.2617-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,258 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 predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 splice_region, intron
• Scores: Splicing: ADA: 0.9899
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• 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: Uncertain_significance. The variant received 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2617-5C>A		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2617-5C>A		splice_region_variant, intron_variant	Intron 18 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2617-5C>A		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2029-5C>A		splice_region_variant, intron_variant	Intron 15 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1261-5C>A		splice_region_variant, intron_variant	Intron 11 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1342-5C>A		splice_region_variant, intron_variant	Intron 11 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1102-5C>A		splice_region_variant, intron_variant	Intron 10 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.970-5C>A		splice_region_variant, intron_variant	Intron 9 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454258 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722890

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

African (AFR) AF: 0.0000300 AC: 1 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 43702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39272

South Asian (SAS) AF: 0.00 AC: 0 AN: 85520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108314

Other (OTH) AF: 0.00 AC: 0 AN: 60132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	18
DANN	Benign	0.51
PhyloP100		-0.15
PromoterAI		0.0066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377743250; hg19: chr19-11132396;