NM_001387283.1:c.3451A>G

Variant names:

• chr19-11030798-A-G
• rs544231909
• NM_001387283.1:c.3451A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001387283.1(SMARCA4):​c.3451A>G​(p.Ile1151Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 1,609,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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 Likely_benign. Variant got -5 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16298288).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3451A>G	p.Ile1151Val	missense_variant	Exon 26 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3451A>G	p.Ile1151Val	missense_variant	Exon 25 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3451A>G	p.Ile1151Val	missense_variant	Exon 26 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2863A>G	p.Ile955Val	missense_variant	Exon 22 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2095A>G	p.Ile699Val	missense_variant	Exon 18 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2176A>G	p.Ile726Val	missense_variant	Exon 18 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1936A>G	p.Ile646Val	missense_variant	Exon 17 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1804A>G	p.Ile602Val	missense_variant	Exon 16 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 240696 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130646

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457426 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724566

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74492

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000826 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Jun 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 C25"). ClinVar contains an entry for this variant (Variation ID: 408705). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs544231909, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1151 of the SMARCA4 protein (p.Ile1151Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.21	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.70	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Benign	0.085
Sift	Benign	0.21	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.50	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.0020	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.17
MutPred		0.38		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;.;.;
MVP		0.42
MPC		1.3
ClinPred		0.47	T
GERP RS		4.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8
Varity_R		0.13
gMVP		0.85

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: rs544231909; hg19: chr19-11141474;