19-10986236-C-T

Position:

• chr19-10986236-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003072.5(SMARCA4):​c.403C>T​(p.Pro135Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.26

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ: 6.8459 (greater than the threshold 3.09). Trascript score misZ: 8.7957 (greater than threshold 3.09). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11807376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.403C>T	p.Pro135Ser	missense_variant	4/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.403C>T	p.Pro135Ser	missense_variant	4/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.403C>T	p.Pro135Ser	missense_variant	4/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.403C>T	p.Pro135Ser	missense_variant	4/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.403C>T	p.Pro135Ser	missense_variant	4/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.403C>T	p.Pro135Ser	missense_variant	5/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.403C>T	p.Pro135Ser	missense_variant	4/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.403C>T	p.Pro135Ser	missense_variant	4/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.403C>T	p.Pro135Ser	missense_variant	5/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461666 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs150949949, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 135 of the SMARCA4 protein (p.Pro135Ser). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2020

The p.P135S variant (also known as c.403C>T), located in coding exon 3 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 403. The proline at codon 135 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.076
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.71
DEOGEN2	Benign	0.34	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	-0.69	N;.;.;.;N;N;.;N;N;N;N;.;N;N;N;N;N;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.59	T;.;.;.;.;.;.;.;.;.;T;.;.;T;.;T;.;T;T
Sift4G	Benign	0.28	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.0010	B;.;D;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;D
Vest4		0.31
MutPred		0.17		Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);
MVP		0.58
MPC		0.89
ClinPred		0.039	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150949949; hg19: chr19-11096912;