NM_001387283.1:c.2541G>C

Variant names:

• chr19-11019626-G-C
• rs1064796361
• NM_001387283.1:c.2541G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001387283.1(SMARCA4):​c.2541G>C​(p.Gln847His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.18

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2541G>C	p.Gln847His	missense_variant	Exon 19 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2541G>C	p.Gln847His	missense_variant	Exon 18 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2541G>C	p.Gln847His	missense_variant	Exon 19 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1953G>C	p.Gln651His	missense_variant	Exon 15 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1185G>C	p.Gln395His	missense_variant	Exon 11 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1266G>C	p.Gln422His	missense_variant	Exon 11 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1026G>C	p.Gln342His	missense_variant	Exon 10 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.894G>C	p.Gln298His	missense_variant	Exon 9 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726612

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

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: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

May 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 847 of the SMARCA4 protein (p.Gln847His). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 423325). 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 not expected to disrupt SMARCA4 protein function with a negative 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. -

not provided Uncertain:1

Feb 09, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q847H variant in the SMARCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q847H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q847H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Q847H as a variant of uncertain significance -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q847H variant (also known as c.2541G>C), located in coding exon 17 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 2541. The glutamine at codon 847 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Benign	0.062
Eigen_PC	Benign	0.0062
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.5	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.024	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.045	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;T;D;.;.;.;.
Polyphen		0.94	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.23
MutPred		0.39		Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);Loss of catalytic residue at Q847 (P = 0.1029);.;Loss of catalytic residue at Q847 (P = 0.1029);.;.;.;.;
MVP		0.82
MPC		3.1
ClinPred		0.95	D
GERP RS		1.9
Varity_R		0.22
gMVP		0.84

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: rs1064796361; hg19: chr19-11130302;