19-11039520-G-C

Variant names:

• chr19-11039520-G-C
• rs780721689
• NM_001387283.1:c.4233G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001387283.1(SMARCA4):​c.4233G>C​(p.Gln1411His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.730

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.14662677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4233G>C	p.Gln1411His	missense_variant	Exon 30 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4171-1787G>C		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.4233G>C	p.Gln1411His	missense_variant	Exon 30 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000643549.1	c.4134G>C	p.Gln1378His	missense_variant	Exon 29 of 35			ENSP00000493975.1
SMARCA4	ENST00000344626.10	c.4171-1787G>C		intron_variant	Intron 29 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000541122.6	c.4072-1778G>C		intron_variant	Intron 29 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4072-1778G>C		intron_variant	Intron 28 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4072-1778G>C		intron_variant	Intron 28 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4072-1778G>C		intron_variant	Intron 29 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3583-1778G>C		intron_variant	Intron 26 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2815-1778G>C		intron_variant	Intron 22 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2797-1778G>C		intron_variant	Intron 21 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2656-1778G>C		intron_variant	Intron 21 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2524-1778G>C		intron_variant	Intron 20 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.328-1778G>C		intron_variant	Intron 3 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451306 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Mar 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1037186). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1411 of the SMARCA4 protein (p.Gln1411His). -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1411H variant (also known as c.4233G>C), located in coding exon 29 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 4233. The glutamine at codon 1411 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	.;T;.;.;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.65	T;.;.;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.65	T
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.040	.;.;.;.;D
Polyphen		0.68	.;P;.;.;P
Vest4		0.21
MutPred		0.28		.;Loss of disorder (P = 0.1098);.;.;Loss of disorder (P = 0.1098);
MVP		0.15
ClinPred		0.19	T
GERP RS		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780721689; hg19: chr19-11150196;