19-10985385-C-T

Position:

• chr19-10985385-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003072.5(SMARCA4):​c.335C>T​(p.Pro112Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.81

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.335C>T	p.Pro112Leu	missense_variant	3/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.335C>T	p.Pro112Leu	missense_variant	3/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.335C>T	p.Pro112Leu	missense_variant	3/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.335C>T	p.Pro112Leu	missense_variant	3/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.335C>T	p.Pro112Leu	missense_variant	3/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.335C>T	p.Pro112Leu	missense_variant	4/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.335C>T	p.Pro112Leu	missense_variant	3/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.335C>T	p.Pro112Leu	missense_variant	3/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.335C>T	p.Pro112Leu	missense_variant	4/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461638 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 389324). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 112 of the SMARCA4 protein (p.Pro112Leu). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2016

The P112L variant in the SMARCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P112L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P112L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P112L as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The p.P112L variant (also known as c.335C>T), located in coding exon 2 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 335. The proline at codon 112 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). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.79	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	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Uncertain	0.052	T;.;.;.;.;.;.;.;.;.;T;.;.;T;D;D;D;T;T
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D
Vest4		0.76
MutPred		0.26		Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);Loss of glycosylation at P112 (P = 0.0314);
MVP		0.73
MPC		0.85
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.46
gMVP		0.52

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: rs1057523400; hg19: chr19-11096061;