19-11060119-C-T

Position:

• chr19-11060119-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP3 BS1_Supporting BS2

The NM_003072.5(SMARCA4):​c.4843C>T​(p.Arg1615Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,398,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.161

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000222 (31/1398594) while in subpopulation SAS AF= 0.000303 (24/79218). AF 95% confidence interval is 0.000208. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4939C>T	p.Arg1647Trp	missense_variant	35/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4843C>T	p.Arg1615Trp	missense_variant	34/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4939C>T	p.Arg1647Trp	missense_variant	35/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4843C>T	p.Arg1615Trp	missense_variant	34/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4849C>T	p.Arg1617Trp	missense_variant	34/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4753C>T	p.Arg1585Trp	missense_variant	34/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4753C>T	p.Arg1585Trp	missense_variant	33/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4753C>T	p.Arg1585Trp	missense_variant	33/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4750C>T	p.Arg1584Trp	missense_variant	34/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4264C>T	p.Arg1422Trp	missense_variant	31/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3493C>T	p.Arg1165Trp	missense_variant	27/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3475C>T	p.Arg1159Trp	missense_variant	26/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3337C>T	p.Arg1113Trp	missense_variant	26/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3103C>T	p.Arg1035Trp	missense_variant	24/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.907C>T	p.Arg303Trp	missense_variant	7/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000131 AC: 2 AN: 152632 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000171

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1398594 Hom.: 0 Cov.: 33 AF XY: 0.0000333 AC XY: 23 AN XY: 689846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1647 of the SMARCA4 protein (p.Arg1647Trp). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 408655). 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 expected to disrupt SMARCA4 protein function with a positive 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The p.R1647W variant (also known as c.4939C>T), located in coding exon 34 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4939. The arginine at codon 1647 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). 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 rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.52
MVP		0.78
MPC		2.2
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.52
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs902428108; hg19: chr19-11170795;