19-11013038-G-T

Variant names:

• chr19-11013038-G-T
• NM_001387283.1:c.2364G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_003072.5(SMARCA4):​c.2364G>T​(p.Gln788His) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q788R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51

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]

ENSG00000266936 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003072.5
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2364G>T	p.Gln788His	missense_variant	Exon 17 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2364G>T	p.Gln788His	missense_variant	Exon 16 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2364G>T	p.Gln788His	missense_variant	Exon 17 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1776G>T	p.Gln592His	missense_variant	Exon 13 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1008G>T	p.Gln336His	missense_variant	Exon 9 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1089G>T	p.Gln363His	missense_variant	Exon 9 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.849G>T	p.Gln283His	missense_variant	Exon 8 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.717G>T	p.Gln239His	missense_variant	Exon 7 of 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	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;H;H;.;H;H;H;H;H;H;H;H;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.96
MutPred		0.88		Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);Gain of glycosylation at K785 (P = 0.2249);.;Gain of glycosylation at K785 (P = 0.2249);.;.;.;.;
MVP		0.97
MPC		3.2
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.99

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: chr19-11123714;