rs746219091

Positions:

• chr19-11033822-C-A
• chr19-11033822-C-G
• chr19-11033822-C-T

Variant summary

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

The NM_003072.5(SMARCA4):​c.3830C>A​(p.Pro1277Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000159 in 627,440 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: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.14

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.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2541863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3830C>A	p.Pro1277Gln	missense_variant	27/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3830C>A	p.Pro1277Gln	missense_variant	27/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3830C>A	p.Pro1277Gln	missense_variant	27/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3830C>A	p.Pro1277Gln	missense_variant	27/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643995.1	c.3242C>A	p.Pro1081Gln	missense_variant	24/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2474C>A	p.Pro825Gln	missense_variant	20/28			ENSP00000495599.1
SMARCA4	ENST00000642350.1	c.2315C>A	p.Pro772Gln	missense_variant	19/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2183C>A	p.Pro728Gln	missense_variant	18/25			ENSP00000494159.1
SMARCA4	ENST00000643549.1	c.3775-301C>A		intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3775-301C>A		intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3775-301C>A		intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3775-301C>A		intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3775-301C>A		intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000644065.1	c.2500-301C>A		intron_variant				ENSP00000493615.1
SMARCA4	ENST00000538456.4	c.31-301C>A		intron_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000159 AC: 1 AN: 627440 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 341862

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: 0.00000286

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	ClinVar contains an entry for this variant (Variation ID: 470369). 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 proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1277 of the SMARCA4 protein (p.Pro1277Gln). 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. -

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

GeneDx

Oct 20, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2020

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	0.077
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;T;T;T;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	.;.;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.0	N;.;N;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.66	N;.;N;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.26	T;.;T;.;.;.
Sift4G	Benign	0.62	T;.;T;T;.;.
Polyphen		0.99	D;B;D;B;.;.
Vest4		0.34
MutPred		0.24		Loss of glycosylation at P1277 (P = 0.0359);Loss of glycosylation at P1277 (P = 0.0359);Loss of glycosylation at P1277 (P = 0.0359);Loss of glycosylation at P1277 (P = 0.0359);.;.;
MVP		0.72
MPC		1.4
ClinPred		0.37	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.63

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: rs746219091; hg19: chr19-11144498;