19-10984277-G-C

Variant names:

• chr19-10984277-G-C
• rs765325777
• NM_001387283.1:c.126G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003072.5(SMARCA4):​c.126G>C​(p.Met42Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,580 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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M42V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.84
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34938186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.126G>C	p.Met42Ile	missense_variant	Exon 2 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.126G>C	p.Met42Ile	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.126G>C	p.Met42Ile	missense_variant	Exon 2 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.126G>C	p.Met42Ile	missense_variant	Exon 2 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.126G>C	p.Met42Ile	missense_variant	Exon 2 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.126G>C	p.Met42Ile	missense_variant	Exon 3 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.126G>C	p.Met42Ile	missense_variant	Exon 2 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.126G>C	p.Met42Ile	missense_variant	Exon 2 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.126G>C	p.Met42Ile	missense_variant	Exon 3 of 35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238198 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458580 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725458

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000450 AC: 2 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52400

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110972

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Mar 24, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 42 of the SMARCA4 protein (p.Met42Ile). This variant is present in population databases (rs765325777, gnomAD 0.003%). 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: 486481). 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. -

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

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M42I variant (also known as c.126G>C), located in coding exon 1 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 126. The methionine at codon 42 is replaced by isoleucine, an amino acid with highly similar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PhyloP100		6.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.028	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Uncertain	0.031	D;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;D;D;D
Polyphen		0.53	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P
Vest4		0.29
MutPred		0.20		Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);Gain of glycosylation at S41 (P = 0.0273);
MVP		0.66
MPC		0.28
ClinPred		0.66	D
GERP RS		3.9
PromoterAI		0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.38
Mutation Taster		=70/30	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: rs765325777; hg19: chr19-11094953;