rs200525458

Variant names:

• chr19-11039546-C-A
• rs200525458
• NM_001387283.1:c.4259C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11039546-C-A
• chr19-11039546-C-G
• chr19-11039546-C-T

Variant summary

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

The NM_001387283.1(SMARCA4):​c.4259C>A​(p.Ala1420Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A1420G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.4259C>A	p.Ala1420Glu	missense	Exon 30 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.4171-1761C>A		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.4259C>A	p.Ala1420Glu	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.4259C>A	p.Ala1420Glu	missense	Exon 30 of 36	ENSP00000495368.1
	SMARCA4	ENST00000643549.1		c.4160C>A	p.Ala1387Glu	missense	Exon 29 of 35	ENSP00000493975.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4171-1761C>A		intron	N/A	ENSP00000343896.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441468 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 716672

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32344

American (AMR) AF: 0.00 AC: 0 AN: 41218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 38552

South Asian (SAS) AF: 0.00 AC: 0 AN: 82434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102768

Other (OTH) AF: 0.00 AC: 0 AN: 59616

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.60
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	1.0	T
Polyphen		0.96	D
Vest4		0.23
MutPred		0.36		Loss of MoRF binding (P = 0.0353)
MVP		0.15
ClinPred		0.29	T
GERP RS		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: -4

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

Other links and lift over

dbSNP: rs200525458; hg19: chr19-11150222;