NM_001387283.1:c.173C>T

Variant names:

• chr19-10984324-C-T
• rs1555750978
• NM_001387283.1:c.173C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387283.1(SMARCA4):​c.173C>T​(p.Thr58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. T58S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.12
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077891916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.173C>T	p.Thr58Ile	missense_variant	Exon 3 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.173C>T	p.Thr58Ile	missense_variant	Exon 2 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.173C>T	p.Thr58Ile	missense_variant	Exon 3 of 35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451964 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721516

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.0000230 AC: 1 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39184

South Asian (SAS) AF: 0.00 AC: 0 AN: 84774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107732

Other (OTH) AF: 0.00 AC: 0 AN: 59912

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 12, 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 isoleucine, which is neutral and non-polar, at codon 58 of the SMARCA4 protein (p.Thr58Ile). This variant is not present in population databases (gnomAD no frequency). 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: 537776). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 Uncertain:1

Dec 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T58I variant (also known as c.173C>T), located in coding exon 1 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 173. The threonine at codon 58 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.55
LIST_S2	Benign	0.0	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.078	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.55	N;.;.;.;N;N;.;N;N;N;N;.;N;N;N;N;N;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
Sift	Uncertain	0.021	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.19	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Vest4		0.24
ClinPred		0.20	T
GERP RS		1.4
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.051
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555750978; hg19: chr19-11095000;