19-11007902-G-C

Variant names:

• chr19-11007902-G-C
• rs1060502105
• NM_001387283.1:c.2002G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003072.5(SMARCA4):​c.2002G>C​(p.Glu668Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. E668K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense, splice_region
• Scores: Splicing: ADA: 0.9957
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.37
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.2002G>C	p.Glu668Gln	missense splice_region	Exon 14 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.2002G>C	p.Glu668Gln	missense splice_region	Exon 14 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.2002G>C	p.Glu668Gln	missense splice_region	Exon 14 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.2002G>C	p.Glu668Gln	missense splice_region	Exon 14 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.2002G>C	p.Glu668Gln	missense splice_region	Exon 14 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.2002G>C	p.Glu668Gln	missense splice_region	Exon 14 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458794 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725708

African (AFR) AF: 0.0000599 AC: 2 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110032

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.058
Sift	Benign	0.077	T
Sift4G	Benign	0.077	T
Polyphen		0.035	B
Vest4		0.45
MutPred		0.28		Loss of helix (P = 0.0558)
MVP		0.60
MPC		1.5
ClinPred		0.87	D
GERP RS		4.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		4.0
Varity_R		0.13
gMVP		0.61
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060502105; hg19: chr19-11118578;