rs747829176

Positions:

• chr19-11058338-A-C
• chr19-11058338-A-G
• chr19-11058338-A-T

Variant summary

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

The NM_003072.5(SMARCA4):​c.4508A>C​(p.Lys1503Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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 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). 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4604A>C	p.Lys1535Thr	missense_variant	32/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4508A>C	p.Lys1503Thr	missense_variant	31/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4604A>C	p.Lys1535Thr	missense_variant	32/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4508A>C	p.Lys1503Thr	missense_variant	31/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4514A>C	p.Lys1505Thr	missense_variant	31/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4418A>C	p.Lys1473Thr	missense_variant	31/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4418A>C	p.Lys1473Thr	missense_variant	30/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4418A>C	p.Lys1473Thr	missense_variant	30/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4415A>C	p.Lys1472Thr	missense_variant	31/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3929A>C	p.Lys1310Thr	missense_variant	28/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3158A>C	p.Lys1053Thr	missense_variant	24/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3140A>C	p.Lys1047Thr	missense_variant	23/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3002A>C	p.Lys1001Thr	missense_variant	23/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2870A>C	p.Lys957Thr	missense_variant	22/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.674A>C	p.Lys225Thr	missense_variant	5/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460834 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726792

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.4	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;N;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.078	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;T;.;.;.;.;.
Sift4G	Benign	0.063	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.054	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.80
MutPred		0.63		.;.;Loss of methylation at K1535 (P = 0.0052);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of methylation at K1535 (P = 0.0052);.;.;.;.;.;
MVP		0.65
MPC		2.2
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs747829176; hg19: chr19-11169014;