NM_001387283.1:c.146C>T

Variant names:

• chr19-10984297-C-T
• rs1464033862
• NM_001387283.1:c.146C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001387283.1(SMARCA4):​c.146C>T​(p.Pro49Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,455,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.146C>T	p.Pro49Leu	missense_variant	Exon 3 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.146C>T	p.Pro49Leu	missense_variant	Exon 2 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.146C>T	p.Pro49Leu	missense_variant	Exon 3 of 35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455820 Hom.: 0 Cov.: 33 AF XY: 0.00000691 AC XY: 5 AN XY: 723860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 49 of the SMARCA4 protein (p.Pro49Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470246). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Dec 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P49L variant (also known as c.146C>T), located in coding exon 1 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 146. The proline at codon 49 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Uncertain	0.020	D;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D
Vest4		0.71
MutPred		0.19		Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);Loss of glycosylation at P49 (P = 0.0094);
MVP		0.81
MPC		0.26
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.097

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

Publications

LitVar

Other links and lift over

dbSNP: rs1464033862; hg19: chr19-11094973; COSMIC: COSV104418460; COSMIC: COSV104418460;