19-11059871-G-C

Variant names:

• chr19-11059871-G-C
• rs148115492
• NM_001387283.1:c.4850G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001387283.1(SMARCA4):​c.4850G>C​(p.Gly1617Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,598 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G1617V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.31
• Publications: 9 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2043879).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000821 (12/1461598) while in subpopulation AMR AF = 0.0000894 (4/44724). AF 95% confidence interval is 0.0000298. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4850G>C	p.Gly1617Ala	missense_variant	Exon 34 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4754G>C	p.Gly1585Ala	missense_variant	Exon 33 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4850G>C	p.Gly1617Ala	missense_variant	Exon 34 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4754G>C	p.Gly1585Ala	missense_variant	Exon 33 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4760G>C	p.Gly1587Ala	missense_variant	Exon 33 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4664G>C	p.Gly1555Ala	missense_variant	Exon 33 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4664G>C	p.Gly1555Ala	missense_variant	Exon 32 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4664G>C	p.Gly1555Ala	missense_variant	Exon 32 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4661G>C	p.Gly1554Ala	missense_variant	Exon 33 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4175G>C	p.Gly1392Ala	missense_variant	Exon 30 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3404G>C	p.Gly1135Ala	missense_variant	Exon 26 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3386G>C	p.Gly1129Ala	missense_variant	Exon 25 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3248G>C	p.Gly1083Ala	missense_variant	Exon 25 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3014G>C	p.Gly1005Ala	missense_variant	Exon 23 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.818G>C	p.Gly273Ala	missense_variant	Exon 6 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248556 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00000821 AC: 12 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Jan 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1617 of the SMARCA4 protein (p.Gly1617Ala). This variant is present in population databases (rs148115492, gnomAD 0.006%). 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: 238487). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1617A variant (also known as c.4850G>C), located in coding exon 33 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 4850. The glycine at codon 1617 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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). 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	Benign	0.18
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.034
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.082	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Vest4		0.39
ClinPred		0.27	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.59
Mutation Taster		=38/62	disease causing

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: rs148115492; hg19: chr19-11170547;