rs201600949

Positions:

• chr19-10986552-C-A
• chr19-10986552-C-G
• chr19-10986552-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.719C>A​(p.Pro240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

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 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). 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=0.118052185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.719C>A	p.Pro240Gln	missense_variant	4/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.719C>A	p.Pro240Gln	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.719C>A	p.Pro240Gln	missense_variant	4/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.719C>A	p.Pro240Gln	missense_variant	4/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.719C>A	p.Pro240Gln	missense_variant	4/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.719C>A	p.Pro240Gln	missense_variant	5/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.719C>A	p.Pro240Gln	missense_variant	4/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.719C>A	p.Pro240Gln	missense_variant	4/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.719C>A	p.Pro240Gln	missense_variant	5/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.131C>A	p.Pro44Gln	missense_variant	1/32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1386750 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684462

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

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The p.P240Q variant (also known as c.719C>A), located in coding exon 3 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 719. The proline at codon 240 is replaced by glutamine, an amino acid with similar properties. 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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.079
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.58
DEOGEN2	Benign	0.20	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.14	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.72	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.26
Sift	Benign	0.23	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.22	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.57	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P
Vest4		0.38
MutPred		0.26		Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);
MVP		0.60
MPC		0.24
ClinPred		0.31	T
GERP RS		3.4
Varity_R		0.039
gMVP		0.11

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: rs201600949; hg19: chr19-11097228;