19-10986489-C-T

Variant names:

• chr19-10986489-C-T
• rs371832808
• NM_001387283.1:c.656C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001387283.1(SMARCA4):​c.656C>T​(p.Thr219Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,550,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T219A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.54
• Publications: 2 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21956816).
• BP6: Variant 19-10986489-C-T is Benign according to our data. Variant chr19-10986489-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 470443.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000394 (6/152202) while in subpopulation AFR AF = 0.000121 (5/41446). AF 95% confidence interval is 0.0000474. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.656C>T	p.Thr219Met	missense	Exon 4 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.656C>T	p.Thr219Met	missense	Exon 4 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.656C>T	p.Thr219Met	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.656C>T	p.Thr219Met	missense	Exon 4 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.656C>T	p.Thr219Met	missense	Exon 4 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.656C>T	p.Thr219Met	missense	Exon 4 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000268 AC: 4 AN: 149100 AF XY: 0.0000250

Gnomad AFR exome AF: 0.000124

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: 0.0000355

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000336 AC: 47 AN: 1398306 Hom.: 0 Cov.: 34 AF XY: 0.0000333 AC XY: 23 AN XY: 690160

African (AFR) AF: 0.0000631 AC: 2 AN: 31720

American (AMR) AF: 0.00 AC: 0 AN: 35894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35914

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000379 AC: 41 AN: 1080472

Other (OTH) AF: 0.0000344 AC: 2 AN: 58060

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.000121 AC: 5 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000678 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000472 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000190 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2 Benign:1

Dec 18, 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 methionine, which is neutral and non-polar, at codon 219 of the SMARCA4 protein (p.Thr219Met). This variant is present in population databases (rs371832808, gnomAD 0.004%). 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: 470443). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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.

Oct 06, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 06, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMARCA4 c.656C>T (p.Thr219Met) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v3.1 (https://gnomad.broadinstitute.org/variant/19-10986489-C-T). This population frequency is higher than expected for a pathogenic variant in SMARCA4 causing Rhabdoid Tumor Predisposition Syndrome (BS1). In silico tools predict a benign effect on the gene or protein function (BP4). This variant has been identified in two individuals without a personal or family history of rhabdoid tumors or Coffin-Siris syndrome (internal data). To our knowledge, this variant has not been reported in individuals with Rhabdoid Tumor Predisposition Syndrome. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4.

not provided Uncertain:1

Mar 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Oct 07, 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	0.10
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.041	D
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.43
MVP		0.57
MPC		0.27
ClinPred		0.26	T
GERP RS		4.4
PromoterAI		-0.013	Neutral
Varity_R		0.054
gMVP		0.078
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs371832808; hg19: chr19-11097165; COSMIC: COSV60790356;