19-11041428-G-T

Position:

• chr19-11041428-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.4292G>T​(p.Arg1431Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,152 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.97

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 3 ACMG points.

• 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.4388G>T	p.Arg1463Leu	missense_variant	31/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4292G>T	p.Arg1431Leu	missense_variant	30/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4388G>T	p.Arg1463Leu	missense_variant	31/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4292G>T	p.Arg1431Leu	missense_variant	30/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4298G>T	p.Arg1433Leu	missense_variant	30/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4202G>T	p.Arg1401Leu	missense_variant	30/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4202G>T	p.Arg1401Leu	missense_variant	29/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4202G>T	p.Arg1401Leu	missense_variant	29/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4202G>T	p.Arg1401Leu	missense_variant	30/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3713G>T	p.Arg1238Leu	missense_variant	27/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2945G>T	p.Arg982Leu	missense_variant	23/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2927G>T	p.Arg976Leu	missense_variant	22/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2786G>T	p.Arg929Leu	missense_variant	22/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2654G>T	p.Arg885Leu	missense_variant	21/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.458G>T	p.Arg153Leu	missense_variant	4/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460152 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726468

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: 8.99e-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	0.70
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.11	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.071	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.49	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.71
MutPred		0.24		.;.;Gain of loop (P = 0.0079);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of loop (P = 0.0079);.;.;.;.;.;
MVP		0.74
MPC		1.5
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.77

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: chr19-11152104;