chr19-11058859-C-G

Position:

• chr19-11058859-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_003072.5(SMARCA4):​c.4605C>G​(p.Asn1535Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1535N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801

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.

• 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). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4701C>G	p.Asn1567Lys	missense_variant	33/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4605C>G	p.Asn1535Lys	missense_variant	32/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4701C>G	p.Asn1567Lys	missense_variant	33/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4605C>G	p.Asn1535Lys	missense_variant	32/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4611C>G	p.Asn1537Lys	missense_variant	32/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4515C>G	p.Asn1505Lys	missense_variant	32/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4515C>G	p.Asn1505Lys	missense_variant	31/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4515C>G	p.Asn1505Lys	missense_variant	31/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4512C>G	p.Asn1504Lys	missense_variant	32/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4026C>G	p.Asn1342Lys	missense_variant	29/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3255C>G	p.Asn1085Lys	missense_variant	25/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3237C>G	p.Asn1079Lys	missense_variant	24/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3099C>G	p.Asn1033Lys	missense_variant	24/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2895+496C>G		intron_variant				ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.699+496C>G		intron_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.13	N
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.00060	D
MutationAssessor	Pathogenic	4.6	H;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.0	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.95
MutPred		0.94		.;.;Gain of methylation at N1567 (P = 0.0258);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of methylation at N1567 (P = 0.0258);.;.;.;.;.;
MVP		0.90
MPC		2.3
ClinPred		1.0	D
GERP RS		-1.6
Varity_R		0.96
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11169535;