rs864622722

Variant names:

• chr19-11041446-GC-AA
• rs864622722
• NM_001387283.1:c.4406_4407delGCinsAA

Variant summary

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

The NM_003072.5(SMARCA4):​c.4310_4311delGCinsAA​(p.Ser1437Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.31

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.4406_4407delGCinsAA	p.Ser1469Lys	missense_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4310_4311delGCinsAA	p.Ser1437Lys	missense_variant		ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4406_4407delGCinsAA	p.Ser1469Lys	missense_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4310_4311delGCinsAA	p.Ser1437Lys	missense_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4316_4317delGCinsAA	p.Ser1439Lys	missense_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4220_4221delGCinsAA	p.Ser1407Lys	missense_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4220_4221delGCinsAA	p.Ser1407Lys	missense_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4220_4221delGCinsAA	p.Ser1407Lys	missense_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4220_4221delGCinsAA	p.Ser1407Lys	missense_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3731_3732delGCinsAA	p.Ser1244Lys	missense_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2963_2964delGCinsAA	p.Ser988Lys	missense_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2945_2946delGCinsAA	p.Ser982Lys	missense_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2804_2805delGCinsAA	p.Ser935Lys	missense_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2672_2673delGCinsAA	p.Ser891Lys	missense_variant				ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.476_477delGCinsAA	p.Ser159Lys	missense_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Sep 06, 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 lysine, which is basic and polar, at codon 1469 of the SMARCA4 protein (p.Ser1469Lys). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 221035). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Mar 19, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Hereditary cancer-predisposing syndrome Benign:1

Jan 12, 2021

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622722; hg19: chr19-11152122;