19-10986515-A-G

Variant names:

• chr19-10986515-A-G
• rs1021610405
• NM_001387283.1:c.682A>G

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.682A>G​(p.Thr228Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,392,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T228K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.14
• 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=0.06883624).
• BP6: Variant 19-10986515-A-G is Benign according to our data. Variant chr19-10986515-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 470446.

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.682A>G	p.Thr228Ala	missense	Exon 4 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.682A>G	p.Thr228Ala	missense	Exon 4 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.682A>G	p.Thr228Ala	missense	Exon 4 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.682A>G	p.Thr228Ala	missense	Exon 4 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.682A>G	p.Thr228Ala	missense	Exon 4 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.682A>G	p.Thr228Ala	missense	Exon 4 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000142 AC: 2 AN: 140690 AF XY: 0.0000262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1392580 Hom.: 0 Cov.: 34 AF XY: 0.00000291 AC XY: 2 AN XY: 687192

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.0000280 AC: 1 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25116

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078862

Other (OTH) AF: 0.00 AC: 0 AN: 57954

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000509 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 228 of the SMARCA4 protein (p.Thr228Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470446). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Hereditary cancer-predisposing syndrome Benign:1

Jan 23, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.16
Sift	Benign	0.50	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.20		Loss of phosphorylation at T228 (P = 0.0065)
MVP		0.52
MPC		0.25
ClinPred		0.037	T
GERP RS		3.9
PromoterAI		-0.0090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.036
gMVP		0.075
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1021610405; hg19: chr19-11097191;