rs1555757541

Positions:

• chr19-10991174-A-C
• chr19-10991174-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003072.5(SMARCA4):​c.1270A>C​(p.Met424Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.29

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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). GenCC has associacion of 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=0.4226861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1270A>C	p.Met424Leu	missense_variant	8/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1270A>C	p.Met424Leu	missense_variant	8/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1270A>C	p.Met424Leu	missense_variant	8/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1270A>C	p.Met424Leu	missense_variant	8/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1270A>C	p.Met424Leu	missense_variant	8/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1270A>C	p.Met424Leu	missense_variant	9/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1270A>C	p.Met424Leu	missense_variant	8/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1270A>C	p.Met424Leu	missense_variant	8/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1270A>C	p.Met424Leu	missense_variant	9/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.682A>C	p.Met228Leu	missense_variant	5/32			ENSP00000496004.1
SMARCA4	ENST00000644065.1	c.-3A>C		upstream_gene_variant				ENSP00000493615.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461486 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727044

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 23, 2022

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 424 of the SMARCA4 protein (p.Met424Leu). This variant is not present in population databases (gnomAD no frequency). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 537777). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2020

The p.M424L variant (also known as c.1270A>C), located in coding exon 7 of the SMARCA4 gene, results from an A to C substitution at nucleotide position 1270. The methionine at codon 424 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.13	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.26	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.089	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.54
MutPred		0.47		Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);Loss of catalytic residue at V420 (P = 0.0273);
MVP		0.69
MPC		2.0
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.46
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555757541; hg19: chr19-11101850;