chr19-11021869-C-G

Position:

• chr19-11021869-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_003072.5(SMARCA4):​c.2761C>G​(p.Leu921Val) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L921F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 165) in uniprot entity SMCA4_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003072.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11021869-C-T is described in Lovd as [Pathogenic].
• 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). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the 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, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2761C>G	p.Leu921Val	missense_variant	19/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2761C>G	p.Leu921Val	missense_variant	19/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2761C>G	p.Leu921Val	missense_variant	19/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2761C>G	p.Leu921Val	missense_variant	19/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2761C>G	p.Leu921Val	missense_variant	19/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2761C>G	p.Leu921Val	missense_variant	20/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2761C>G	p.Leu921Val	missense_variant	19/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2761C>G	p.Leu921Val	missense_variant	19/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2761C>G	p.Leu921Val	missense_variant	20/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2173C>G	p.Leu725Val	missense_variant	16/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1405C>G	p.Leu469Val	missense_variant	12/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1486C>G	p.Leu496Val	missense_variant	12/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1246C>G	p.Leu416Val	missense_variant	11/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1114C>G	p.Leu372Val	missense_variant	10/25			ENSP00000494159.1

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	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.77
MutPred		0.78		Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);Gain of methylation at K917 (P = 0.078);.;Gain of methylation at K917 (P = 0.078);.;.;.;.;
MVP		0.93
MPC		2.7
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
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: chr19-11132545;