19-11041472-C-T

Position:

• chr19-11041472-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.4336C>T​(p.Pro1446Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4432C>T	p.Pro1478Ser	missense_variant	31/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4336C>T	p.Pro1446Ser	missense_variant	30/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4432C>T	p.Pro1478Ser	missense_variant	31/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4336C>T	p.Pro1446Ser	missense_variant	30/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4342C>T	p.Pro1448Ser	missense_variant	30/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4246C>T	p.Pro1416Ser	missense_variant	30/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4246C>T	p.Pro1416Ser	missense_variant	29/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4246C>T	p.Pro1416Ser	missense_variant	29/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4246C>T	p.Pro1416Ser	missense_variant	30/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3757C>T	p.Pro1253Ser	missense_variant	27/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2989C>T	p.Pro997Ser	missense_variant	23/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2971C>T	p.Pro991Ser	missense_variant	22/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2830C>T	p.Pro944Ser	missense_variant	22/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2698C>T	p.Pro900Ser	missense_variant	21/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.502C>T	p.Pro168Ser	missense_variant	4/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460540 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726596

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. This sequence change replaces proline with serine at codon 1478 of the SMARCA4 protein (p.Pro1478Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.088	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.098	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.77	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.60
MutPred		0.27		.;.;Gain of phosphorylation at P1478 (P = 2e-04);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at P1478 (P = 2e-04);.;.;.;.;.;
MVP		0.48
MPC		2.2
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.79

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: rs1555788318; hg19: chr19-11152148;