rs369724341

Positions:

• chr19-11019647-C-A
• chr19-11019647-C-G
• chr19-11019647-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_003072.5(SMARCA4):​c.2562C>A​(p.Asn854Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: -2.82

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 5 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with DLX1 (size 79) in uniprot entity SMCA4_HUMAN there are 7 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2562C>A	p.Asn854Lys	missense_variant	18/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2562C>A	p.Asn854Lys	missense_variant	18/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2562C>A	p.Asn854Lys	missense_variant	18/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2562C>A	p.Asn854Lys	missense_variant	18/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2562C>A	p.Asn854Lys	missense_variant	18/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2562C>A	p.Asn854Lys	missense_variant	19/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2562C>A	p.Asn854Lys	missense_variant	18/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2562C>A	p.Asn854Lys	missense_variant	18/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2562C>A	p.Asn854Lys	missense_variant	19/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1974C>A	p.Asn658Lys	missense_variant	15/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1206C>A	p.Asn402Lys	missense_variant	11/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1287C>A	p.Asn429Lys	missense_variant	11/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1047C>A	p.Asn349Lys	missense_variant	10/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.915C>A	p.Asn305Lys	missense_variant	9/25			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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.4	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0090	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.86
MutPred		0.65		Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);Gain of methylation at N854 (P = 0.0037);.;Gain of methylation at N854 (P = 0.0037);.;.;.;.;
MVP		0.87
MPC		3.5
ClinPred		0.98	D
GERP RS		-7.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.96
gMVP		0.97

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: chr19-11130323;