19-11060123-C-A

Position:

• chr19-11060123-C-A

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.4847C>A​(p.Pro1616Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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=0.17473188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4943C>A	p.Pro1648Gln	missense_variant	35/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4847C>A	p.Pro1616Gln	missense_variant	34/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4943C>A	p.Pro1648Gln	missense_variant	35/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4847C>A	p.Pro1616Gln	missense_variant	34/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4853C>A	p.Pro1618Gln	missense_variant	34/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4757C>A	p.Pro1586Gln	missense_variant	34/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4757C>A	p.Pro1586Gln	missense_variant	33/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4757C>A	p.Pro1586Gln	missense_variant	33/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4754C>A	p.Pro1585Gln	missense_variant	34/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4268C>A	p.Pro1423Gln	missense_variant	31/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3497C>A	p.Pro1166Gln	missense_variant	27/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3479C>A	p.Pro1160Gln	missense_variant	26/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3341C>A	p.Pro1114Gln	missense_variant	26/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3107C>A	p.Pro1036Gln	missense_variant	24/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.911C>A	p.Pro304Gln	missense_variant	7/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398608 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689868

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 09, 2024

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1648 of the SMARCA4 protein (p.Pro1648Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 665850). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0087	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.92	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	-0.090	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.24	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.21	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.60	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.026	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.16
MutPred		0.30		.;.;Loss of glycosylation at P1648 (P = 0.0382);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of glycosylation at P1648 (P = 0.0382);.;.;.;.;
MVP		0.53
MPC		0.95
ClinPred		0.57	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.087
gMVP		0.56

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: rs878854234; hg19: chr19-11170799;