rs1060502100

Variant names:

• chr19-11039540-C-T
• rs1060502100
• NM_001387283.1:c.4253C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001387283.1(SMARCA4):​c.4253C>T​(p.Thr1418Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1418A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.603
• 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: ClinGen, Orphanet, 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: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16238046).
• BP6: Variant 19-11039540-C-T is Benign according to our data. Variant chr19-11039540-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408693.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.4253C>T	p.Thr1418Ile	missense	Exon 30 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.4171-1767C>T		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.4253C>T	p.Thr1418Ile	missense	Exon 30 of 36	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.4253C>T	p.Thr1418Ile	missense	Exon 30 of 36	ENSP00000495368.1
	SMARCA4	ENST00000643549.1		c.4154C>T	p.Thr1385Ile	missense	Exon 29 of 35	ENSP00000493975.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4171-1767C>T		intron	N/A	ENSP00000343896.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446168 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 719024

African (AFR) AF: 0.0000307 AC: 1 AN: 32562

American (AMR) AF: 0.00 AC: 0 AN: 41912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 38730

South Asian (SAS) AF: 0.00 AC: 0 AN: 83106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105332

Other (OTH) AF: 0.00 AC: 0 AN: 59800

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.58	T
PhyloP100		0.60
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.18	T
Polyphen		0.82	P
Vest4		0.26
MutPred		0.34		Loss of phosphorylation at T1418 (P = 0.028)
MVP		0.13
ClinPred		0.32	T
GERP RS		0.73
Mutation Taster		=100/0	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: rs1060502100; hg19: chr19-11150216;