rs375884151

Positions:

• chr19-10984271-C-G
• chr19-10984271-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_003072.5(SMARCA4):​c.120C>G​(p.His40Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., 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:5
• Conservation: PhyloP100: 1.23

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 Uncertain_significance. Variant got 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.120C>G	p.His40Gln	missense_variant	2/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.120C>G	p.His40Gln	missense_variant	2/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.120C>G	p.His40Gln	missense_variant	2/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.120C>G	p.His40Gln	missense_variant	2/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.120C>G	p.His40Gln	missense_variant	2/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.120C>G	p.His40Gln	missense_variant	3/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.120C>G	p.His40Gln	missense_variant	2/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.120C>G	p.His40Gln	missense_variant	2/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.120C>G	p.His40Gln	missense_variant	3/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152216 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000836 AC: 2 AN: 239156 Hom.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 130742

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458960 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725672

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

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	Mar 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 537780). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 40 of the SMARCA4 protein (p.His40Gln). -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 23, 2023

This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000025 (3/120988 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The p.H40Q variant (also known as c.120C>G), located in coding exon 1 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 120. The histidine at codon 40 is replaced by glutamine, an amino acid with highly similar 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	.;D;.;.;.;.;D;.;.;.;D;T;.;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.38	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.93	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P
Vest4		0.74
MutPred		0.23		Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);Loss of catalytic residue at H40 (P = 0.0614);
MVP		0.77
MPC		0.26
ClinPred		0.66	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.077

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: rs375884151; hg19: chr19-11094947;