rs1555777820

Variant names:

• chr19-11019685-A-G
• rs1555777820
• NM_001387283.1:c.2600A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_003072.5(SMARCA4):​c.2600A>G​(p.Lys867Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.22

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_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2600A>G	p.Lys867Arg	missense_variant	Exon 18 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2600A>G	p.Lys867Arg	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.2600A>G	p.Lys867Arg	missense_variant	Exon 18 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2600A>G	p.Lys867Arg	missense_variant	Exon 18 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2600A>G	p.Lys867Arg	missense_variant	Exon 18 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2600A>G	p.Lys867Arg	missense_variant	Exon 19 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2600A>G	p.Lys867Arg	missense_variant	Exon 18 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2600A>G	p.Lys867Arg	missense_variant	Exon 18 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2600A>G	p.Lys867Arg	missense_variant	Exon 19 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2012A>G	p.Lys671Arg	missense_variant	Exon 15 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1244A>G	p.Lys415Arg	missense_variant	Exon 11 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1325A>G	p.Lys442Arg	missense_variant	Exon 11 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1085A>G	p.Lys362Arg	missense_variant	Exon 10 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.953A>G	p.Lys318Arg	missense_variant	Exon 9 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Sep 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine with arginine at codon 867 of the SMARCA4 protein (p.Lys867Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K867R variant (also known as c.2600A>G), located in coding exon 17 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2600. The lysine at codon 867 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. 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	0.46
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.070	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Benign	0.42	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.;.
Sift4G	Benign	0.45	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.38
MutPred		0.76		Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);Gain of MoRF binding (P = 0.0797);.;Gain of MoRF binding (P = 0.0797);.;.;.;.;
MVP		0.92
MPC		2.9
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.44
gMVP		0.85

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: rs1555777820; hg19: chr19-11130361;