ENST00000643549.1:c.4169C>T

Variant names:

• chr19-11041299-C-T
• ENST00000643549.1:c.4169C>T

Variant summary

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

The ENST00000643549.1(SMARCA4):​c.4169C>T​(p.Thr1390Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. T1390A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 ENST00000643549.1 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68

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 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: 8.7967 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4267-8C>T		splice_region_variant, intron_variant	Intron 30 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4171-8C>T		splice_region_variant, intron_variant	Intron 29 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000643549.1	c.4169C>T	p.Thr1390Ile	missense_variant, splice_region_variant	Exon 30 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4073C>T	p.Thr1358Ile	missense_variant, splice_region_variant	Exon 30 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4073C>T	p.Thr1358Ile	missense_variant, splice_region_variant	Exon 29 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4073C>T	p.Thr1358Ile	missense_variant, splice_region_variant	Exon 29 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4073C>T	p.Thr1358Ile	missense_variant, splice_region_variant	Exon 30 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3584C>T	p.Thr1195Ile	missense_variant, splice_region_variant	Exon 27 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2816C>T	p.Thr939Ile	missense_variant, splice_region_variant	Exon 23 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2798C>T	p.Thr933Ile	missense_variant, splice_region_variant	Exon 22 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2657C>T	p.Thr886Ile	missense_variant, splice_region_variant	Exon 22 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2525C>T	p.Thr842Ile	missense_variant, splice_region_variant	Exon 21 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.329C>T	p.Thr110Ile	missense_variant, splice_region_variant	Exon 4 of 8	3		ENSP00000495197.1
SMARCA4	ENST00000646693.2	c.4267-8C>T		splice_region_variant, intron_variant	Intron 30 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4171-8C>T		splice_region_variant, intron_variant	Intron 29 of 34	1	NM_003072.5	ENSP00000343896.4

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
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0061	.;.;.;.;.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.50	T;.;.;T;T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.036	D
REVEL	Benign	0.27
Sift4G	Uncertain	0.012	.;.;.;D;D;D;.
Vest4		0.58, 0.56, 0.34
MVP		0.49
ClinPred		0.81	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: chr19-11151975;