19-11039521-C-T

Variant names:

• chr19-11039521-C-T
• rs747852149
• NM_001387283.1:c.4234C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001387283.1(SMARCA4):​c.4234C>T​(p.Arg1412Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,602,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.214

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14070818).
• BP6: Variant 19-11039521-C-T is Benign according to our data. Variant chr19-11039521-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238457.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000186 (27/1450176) while in subpopulation SAS AF= 0.000155 (13/83758). AF 95% confidence interval is 0.0000913. There are 1 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4234C>T	p.Arg1412Cys	missense_variant	Exon 30 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4171-1786C>T		intron_variant	Intron 29 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4234C>T	p.Arg1412Cys	missense_variant	Exon 30 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000643549.1	c.4135C>T	p.Arg1379Cys	missense_variant	Exon 29 of 35			ENSP00000493975.1
SMARCA4	ENST00000344626.10	c.4171-1786C>T		intron_variant	Intron 29 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000541122.6	c.4072-1777C>T		intron_variant	Intron 29 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4072-1777C>T		intron_variant	Intron 28 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4072-1777C>T		intron_variant	Intron 28 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4072-1777C>T		intron_variant	Intron 29 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3583-1777C>T		intron_variant	Intron 26 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2815-1777C>T		intron_variant	Intron 22 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2797-1777C>T		intron_variant	Intron 21 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2656-1777C>T		intron_variant	Intron 21 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2524-1777C>T		intron_variant	Intron 20 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.328-1777C>T		intron_variant	Intron 3 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000300 AC: 7 AN: 233438 Hom.: 0 AF XY: 0.0000470 AC XY: 6 AN XY: 127738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000591

Gnomad SAS exome AF: 0.000213

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1450176 Hom.: 1 Cov.: 29 AF XY: 0.0000194 AC XY: 14 AN XY: 721194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000155

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000498 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1412 of the SMARCA4 protein (p.Arg1412Cys). This variant is present in population databases (rs747852149, gnomAD 0.02%). 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: 238457). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

not provided Uncertain:1

May 24, 2022

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 -

Hereditary cancer-predisposing syndrome Benign:1

Dec 13, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.1
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T;.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.76	T;.;.;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.46	T
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.0020	.;.;.;.;D
Polyphen		0.98	.;D;.;.;D
Vest4		0.26
MutPred		0.43		.;Loss of MoRF binding (P = 0.0051);.;.;Loss of MoRF binding (P = 0.0051);
MVP		0.14
ClinPred		0.15	T
GERP RS		-0.78

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: rs747852149; hg19: chr19-11150197;