rs767743765

Variant names:

• chr19-11018973-G-A
• rs767743765
• NM_001387283.1:c.2455G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11018973-G-A
• chr19-11018973-G-C
• chr19-11018973-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 5P and 11B. PM1 PM2 PP2 BP4_Moderate BP6 BS1 BS2

The NM_003072.5(SMARCA4):​c.2455G>A​(p.Ala819Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,716 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: 0.0000034 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.74

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.

• PM1: In a domain Helicase ATP-binding (size 165) in uniprot entity SMCA4_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003072.5
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24818218).
• BP6: Variant 19-11018973-G-A is Benign according to our data. Variant chr19-11018973-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 484839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000342 (5/1461716) while in subpopulation MID AF= 0.000347 (2/5768). AF 95% confidence interval is 0.0000609. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2455G>A	p.Ala819Thr	missense_variant	Exon 18 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2455G>A	p.Ala819Thr	missense_variant	Exon 18 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1867G>A	p.Ala623Thr	missense_variant	Exon 14 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1099G>A	p.Ala367Thr	missense_variant	Exon 10 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1180G>A	p.Ala394Thr	missense_variant	Exon 10 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.940G>A	p.Ala314Thr	missense_variant	Exon 9 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.808G>A	p.Ala270Thr	missense_variant	Exon 8 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727174

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

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

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 819 of the SMARCA4 protein (p.Ala819Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 484839). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Hereditary cancer-predisposing syndrome Benign:1

Apr 24, 2023

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	0.090
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.42
DEOGEN2	Uncertain	0.53	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	0.84	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.15	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.74	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.;.
Sift4G	Benign	0.70	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.0020	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.23
MutPred		0.38		Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);.;Loss of stability (P = 0.1653);.;.;.;.;
MVP		0.78
MPC		1.8
ClinPred		0.17	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.25
gMVP		0.78

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: rs767743765; hg19: chr19-11129649; COSMIC: COSV60810197; COSMIC: COSV60810197;