rs138097741

Positions:

• chr19-10987720-C-A
• chr19-10987720-C-G
• chr19-10987720-C-T

Variant summary

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

The NM_003072.5(SMARCA4):​c.914C>A​(p.Pro305Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,080 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P305P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80

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.914C>A	p.Pro305Gln	missense_variant	6/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.914C>A	p.Pro305Gln	missense_variant	6/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.914C>A	p.Pro305Gln	missense_variant	6/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.914C>A	p.Pro305Gln	missense_variant	6/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.914C>A	p.Pro305Gln	missense_variant	6/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.914C>A	p.Pro305Gln	missense_variant	7/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.914C>A	p.Pro305Gln	missense_variant	6/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.914C>A	p.Pro305Gln	missense_variant	6/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.914C>A	p.Pro305Gln	missense_variant	7/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.326C>A	p.Pro109Gln	missense_variant	3/32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458080 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725262

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: 0.00000180

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	Benign	0.31
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.071	T
MutationAssessor	Uncertain	2.0	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.097	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.38	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.93	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D
Vest4		0.56
MutPred		0.24		Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);Loss of catalytic residue at P305 (P = 0.005);
MVP		0.70
MPC		0.52
ClinPred		0.87	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.13
gMVP		0.25

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: chr19-11098396;