19-10991307-G-T

Variant names:

• chr19-10991307-G-T
• NM_001387283.1:c.1403G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003072.5(SMARCA4):​c.1403G>T​(p.Arg468Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.89

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 Uncertain_significance. Variant got 4 ACMG points.

• 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, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1403G>T	p.Arg468Leu	missense_variant	Exon 9 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1403G>T	p.Arg468Leu	missense_variant	Exon 8 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1403G>T	p.Arg468Leu	missense_variant	Exon 9 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.815G>T	p.Arg272Leu	missense_variant	Exon 5 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.131G>T	p.Arg44Leu	missense_variant	Exon 1 of 27			ENSP00000493615.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449592 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.1	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Benign	0.066	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.69
MutPred		0.58		Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);Gain of ubiquitination at K467 (P = 0.0301);
MVP		0.68
MPC		2.7
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		1.0

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: chr19-11101983; COSMIC: COSV100758796; COSMIC: COSV100758796;