19-11034171-C-T

Position:

• chr19-11034171-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_003072.5(SMARCA4):​c.3922C>T​(p.Arg1308Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.66

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 Pathogenic. Variant got 13 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 19-11034171-C-T is Pathogenic according to our data. Variant chr19-11034171-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3922C>T	p.Arg1308Trp	missense_variant	28/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3922C>T	p.Arg1308Trp	missense_variant	28/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3922C>T	p.Arg1308Trp	missense_variant	28/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3922C>T	p.Arg1308Trp	missense_variant	28/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3823C>T	p.Arg1275Trp	missense_variant	27/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3823C>T	p.Arg1275Trp	missense_variant	28/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3823C>T	p.Arg1275Trp	missense_variant	27/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3823C>T	p.Arg1275Trp	missense_variant	27/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3823C>T	p.Arg1275Trp	missense_variant	28/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3334C>T	p.Arg1112Trp	missense_variant	25/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2566C>T	p.Arg856Trp	missense_variant	21/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2548C>T	p.Arg850Trp	missense_variant	20/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2407C>T	p.Arg803Trp	missense_variant	20/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2275C>T	p.Arg759Trp	missense_variant	19/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.79C>T	p.Arg27Trp	missense_variant	2/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 01, 2016	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28807864, 34615535) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.3	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.91
MutPred		0.55		Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;.;.;.;.;.;Gain of helix (P = 0.0325);.;.;.;.;.;.;Gain of helix (P = 0.0325);.;.;.;.;
MVP		0.95
MPC		2.8
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.98

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: rs587779750; hg19: chr19-11144847; COSMIC: COSV60790070; COSMIC: COSV60790070;