chr19-10995924-C-G

Variant names:

• chr19-10995924-C-G
• rs11672232
• NM_001387283.1:c.1594-289C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387283.1(SMARCA4):​c.1594-289C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 322,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.356
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09082833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1594-289C>G		intron_variant	Intron 9 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1594-289C>G		intron_variant	Intron 9 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1594-289C>G		intron_variant	Intron 9 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1594-289C>G		intron_variant	Intron 9 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1594-289C>G		intron_variant	Intron 9 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1594-289C>G		intron_variant	Intron 10 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1594-289C>G		intron_variant	Intron 9 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1594-289C>G		intron_variant	Intron 9 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1594-289C>G		intron_variant	Intron 10 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1006-289C>G		intron_variant	Intron 6 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.238-289C>G		intron_variant	Intron 2 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.322-289C>G		intron_variant	Intron 2 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.82-289C>G		intron_variant	Intron 1 of 26			ENSP00000495355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000310 AC: 1 AN: 322780 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 174364

African (AFR) AF: 0.00 AC: 0 AN: 9504

American (AMR) AF: 0.00 AC: 0 AN: 17298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9610

East Asian (EAS) AF: 0.00 AC: 0 AN: 18370

South Asian (SAS) AF: 0.00 AC: 0 AN: 46266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2968

European-Non Finnish (NFE) AF: 0.00000538 AC: 1 AN: 185810

Other (OTH) AF: 0.00 AC: 0 AN: 17668

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.73
DANN	Benign	0.69
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.36
Sift4G	Uncertain	0.0090	D
Vest4		0.11
MVP		0.25
ClinPred		0.12	T
GERP RS		-5.0
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs11672232; hg19: chr19-11106600;