rs1555783190

Positions:

• chr19-11030789-G-A
• chr19-11030789-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_003072.5(SMARCA4):​c.3442G>A​(p.Glu1148Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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 4 ACMG points.

• PM1: In a domain Helicase C-terminal (size 162) in uniprot entity SMCA4_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_003072.5
• 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=0.38557017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3442G>A	p.Glu1148Lys	missense_variant	25/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3442G>A	p.Glu1148Lys	missense_variant	25/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3442G>A	p.Glu1148Lys	missense_variant	25/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3442G>A	p.Glu1148Lys	missense_variant	25/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3442G>A	p.Glu1148Lys	missense_variant	25/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3442G>A	p.Glu1148Lys	missense_variant	26/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3442G>A	p.Glu1148Lys	missense_variant	25/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3442G>A	p.Glu1148Lys	missense_variant	25/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3442G>A	p.Glu1148Lys	missense_variant	26/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2854G>A	p.Glu952Lys	missense_variant	22/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2086G>A	p.Glu696Lys	missense_variant	18/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2167G>A	p.Glu723Lys	missense_variant	18/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1927G>A	p.Glu643Lys	missense_variant	17/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1795G>A	p.Glu599Lys	missense_variant	16/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.65	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;D;N;.;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.13	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;D;T;.;.;.
Sift4G	Benign	0.16	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.028	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.55
MutPred		0.38		Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);Gain of methylation at E1148 (P = 0.0122);.;Gain of methylation at E1148 (P = 0.0122);.;.;.;
MVP		0.81
MPC		1.9
ClinPred		0.62	D
GERP RS		4.6
Varity_R		0.30
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11141465;