19-11041530-T-G

Variant names:

• chr19-11041530-T-G
• rs1377505488
• NM_001387283.1:c.4490T>G

Variant summary

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

The NM_001387283.1(SMARCA4):​c.4490T>G​(p.Ile1497Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1497T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4490T>G	p.Ile1497Ser	missense_variant	Exon 31 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4394T>G	p.Ile1465Ser	missense_variant	Exon 30 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4490T>G	p.Ile1497Ser	missense_variant	Exon 31 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4394T>G	p.Ile1465Ser	missense_variant	Exon 30 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4400T>G	p.Ile1467Ser	missense_variant	Exon 30 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4304T>G	p.Ile1435Ser	missense_variant	Exon 30 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4304T>G	p.Ile1435Ser	missense_variant	Exon 29 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4304T>G	p.Ile1435Ser	missense_variant	Exon 29 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4304T>G	p.Ile1435Ser	missense_variant	Exon 30 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3815T>G	p.Ile1272Ser	missense_variant	Exon 27 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3047T>G	p.Ile1016Ser	missense_variant	Exon 23 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3029T>G	p.Ile1010Ser	missense_variant	Exon 22 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2888T>G	p.Ile963Ser	missense_variant	Exon 22 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2756T>G	p.Ile919Ser	missense_variant	Exon 21 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.560T>G	p.Ile187Ser	missense_variant	Exon 4 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000206 AC: 3 AN: 1458840 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725854

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

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110098

Other (OTH) AF: 0.0000166 AC: 1 AN: 60258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000965894), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.76
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.88
gMVP		0.99
Mutation Taster		=25/75	disease causing

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: rs1377505488; hg19: chr19-11152206;