19-10984297-C-T

Variant names:

• chr19-10984297-C-T
• rs1464033862
• NM_001387283.1:c.146C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003072.5(SMARCA4):​c.146C>T​(p.Pro49Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,455,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P49R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.86
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.146C>T	p.Pro49Leu	missense	Exon 2 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.146C>T	p.Pro49Leu	missense	Exon 2 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.146C>T	p.Pro49Leu	missense	Exon 2 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.146C>T	p.Pro49Leu	missense	Exon 2 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.146C>T	p.Pro49Leu	missense	Exon 2 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.146C>T	p.Pro49Leu	missense	Exon 2 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 232110 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455820 Hom.: 0 Cov.: 33 AF XY: 0.00000691 AC XY: 5 AN XY: 723860

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 43984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 85340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109718

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.19		Loss of glycosylation at P49 (P = 0.0094)
MVP		0.81
MPC		0.26
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.097
Mutation Taster		=61/39	polymorphism

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: rs1464033862; hg19: chr19-11094973; COSMIC: COSV104418460; COSMIC: COSV104418460;