NM_001387283.1:c.2084G>A

Variant names:

• chr19-11007984-G-A
• rs755519197
• NM_001387283.1:c.2084G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001387283.1(SMARCA4):​c.2084G>A​(p.Ser695Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.64

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 Likely_benign. Variant got -6 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=0.2413666).
• BP6: Variant 19-11007984-G-A is Benign according to our data. Variant chr19-11007984-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408632.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2084G>A	p.Ser695Asn	missense_variant	Exon 15 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2084G>A	p.Ser695Asn	missense_variant	Exon 14 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2084G>A	p.Ser695Asn	missense_variant	Exon 15 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1496G>A	p.Ser499Asn	missense_variant	Exon 11 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.728G>A	p.Ser243Asn	missense_variant	Exon 7 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.809G>A	p.Ser270Asn	missense_variant	Exon 7 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.569G>A	p.Ser190Asn	missense_variant	Exon 6 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.437G>A	p.Ser146Asn	missense_variant	Exon 5 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251132 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135740

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727038

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 695 of the SMARCA4 protein (p.Ser695Asn). This variant is present in population databases (rs755519197, 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: 408632). 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. -

Hereditary cancer-predisposing syndrome Benign:1

Oct 25, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Benign	1.9	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.48	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.095	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.26	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.29	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.49
MutPred		0.15		Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);Loss of phosphorylation at S695 (P = 0.0063);.;Loss of phosphorylation at S695 (P = 0.0063);.;.;.;
MVP		0.75
MPC		1.5
ClinPred		0.31	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.17
gMVP		0.77

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: rs755519197; hg19: chr19-11118660;