chr19-10994889-C-T

Variant names:

• chr19-10994889-C-T
• rs1060502098
• NM_001387283.1:c.1481C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_003072.5(SMARCA4):​c.1481C>T​(p.Thr494Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T494T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.42
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• otosclerosis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18553635).
• BP6: Variant 19-10994889-C-T is Benign according to our data. Variant chr19-10994889-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408682.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003072.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.1481C>T	p.Thr494Ile	missense	Exon 9 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.1481C>T	p.Thr494Ile	missense	Exon 9 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.1481C>T	p.Thr494Ile	missense	Exon 9 of 36	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.1481C>T	p.Thr494Ile	missense	Exon 9 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1481C>T	p.Thr494Ile	missense	Exon 9 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.1481C>T	p.Thr494Ile	missense	Exon 9 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Intellectual disability, autosomal dominant 16 (1)
-	1	-	not provided (1)
-	1	-	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.30	T
Sift4G	Benign	0.43	T
Polyphen		0.073	B
Vest4		0.27
MutPred		0.48		Gain of catalytic residue at T494 (P = 0.0068)
MVP		0.75
MPC		2.4
ClinPred		0.78	D
GERP RS		4.5
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.95
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs1060502098; hg19: chr19-11105565;