rs367601832

Positions:

• chr19-10984285-C-A
• chr19-10984285-C-G
• chr19-10984285-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_003072.5(SMARCA4):​c.134C>A​(p.Pro45His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.91

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.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.134C>A	p.Pro45His	missense_variant	2/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.134C>A	p.Pro45His	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.134C>A	p.Pro45His	missense_variant	2/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.134C>A	p.Pro45His	missense_variant	2/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.134C>A	p.Pro45His	missense_variant	2/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.134C>A	p.Pro45His	missense_variant	3/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.134C>A	p.Pro45His	missense_variant	2/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.134C>A	p.Pro45His	missense_variant	2/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.134C>A	p.Pro45His	missense_variant	3/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457594 Hom.: 0 Cov.: 33 AF XY: 0.00000690 AC XY: 5 AN XY: 724886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 45 of the SMARCA4 protein (p.Pro45His). This variant is present in population databases (rs367601832, 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: 238372). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2023	This variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.134C>A (p.P45H) alteration is located in exon 2 (coding exon 1) of the SMARCA4 gene. This alteration results from a C to A substitution at nucleotide position 134, causing the proline (P) at amino acid position 45 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SMARCA4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

The SMARCA4 c.134C>A variant is predicted to result in the amino acid substitution p.Pro45His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D
Vest4		0.60
MutPred		0.18		Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);Gain of catalytic residue at P45 (P = 0.0254);
MVP		0.73
MPC		0.29
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.093

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: rs367601832; hg19: chr19-11094961;