rs751373738

Positions:

• chr19-11033445-C-A
• chr19-11033445-C-G
• chr19-11033445-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_003072.5(SMARCA4):​c.3702C>A​(p.Phe1234Leu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.64

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 Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3702C>A	p.Phe1234Leu	missense_variant	26/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3702C>A	p.Phe1234Leu	missense_variant	26/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3702C>A	p.Phe1234Leu	missense_variant	26/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3702C>A	p.Phe1234Leu	missense_variant	26/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3702C>A	p.Phe1234Leu	missense_variant	26/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3702C>A	p.Phe1234Leu	missense_variant	27/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3702C>A	p.Phe1234Leu	missense_variant	26/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3702C>A	p.Phe1234Leu	missense_variant	26/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3702C>A	p.Phe1234Leu	missense_variant	27/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3114C>A	p.Phe1038Leu	missense_variant	23/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2346C>A	p.Phe782Leu	missense_variant	19/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2427C>A	p.Phe809Leu	missense_variant	19/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2187C>A	p.Phe729Leu	missense_variant	18/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2055C>A	p.Phe685Leu	missense_variant	17/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.-43C>A		upstream_gene_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.34	N
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.2	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.2	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.
Polyphen		0.69	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.
Vest4		0.84
MutPred		0.73		Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);Gain of MoRF binding (P = 0.1211);.;Gain of MoRF binding (P = 0.1211);.;.;.;
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.80
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-11144121; COSMIC: COSV60791545; COSMIC: COSV60791545;