19-11035149-C-T

Position:

chr19-11035149-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003072.5(SMARCA4):c.4170+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,602,714 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 23 hom. )

Consequence

SMARCA4
NM_003072.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.129

Variant links:

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 links:

SMARCA4 (HGNC:):

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-11035149-C-T is Benign according to our data. Variant chr19-11035149-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 380708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11035149-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00272 (414/152342) while in subpopulation NFE AF= 0.00489 (333/68040). AF 95% confidence interval is 0.00446. There are 2 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 414 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.4170+17C>T		intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 linkuse as main transcript	c.4170+17C>T		intron_variant		ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.4170+17C>T	intron_variant		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.4170+17C>T	intron_variant	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 linkuse as main transcript	c.4071+17C>T	intron_variant			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 linkuse as main transcript	c.4071+17C>T	intron_variant	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 linkuse as main transcript	c.4071+17C>T	intron_variant			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 linkuse as main transcript	c.4071+17C>T	intron_variant			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 linkuse as main transcript	c.4071+17C>T	intron_variant	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 linkuse as main transcript	c.3582+17C>T	intron_variant			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 linkuse as main transcript	c.2814+17C>T	intron_variant			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 linkuse as main transcript	c.2796+17C>T	intron_variant			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 linkuse as main transcript	c.2655+17C>T	intron_variant			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 linkuse as main transcript	c.2523+17C>T	intron_variant			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 linkuse as main transcript	c.327+17C>T	intron_variant	3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

414

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00334

AC:

772

AN:

231374

Hom.:

AF XY:

0.00342

AC XY:

433

AN XY:

126768

show subpopulations

Gnomad AFR exome

AF:

0.000996

Gnomad AMR exome

AF:

0.000391

Gnomad ASJ exome

AF:

0.000414

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000681

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00637

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00469

AC:

6797

AN:

1450372

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

3316

AN XY:

721452

show subpopulations

Gnomad4 AFR exome

AF:

0.000662

Gnomad4 AMR exome

AF:

0.000410

Gnomad4 ASJ exome

AF:

0.000809

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000469

Gnomad4 FIN exome

AF:

0.00368

Gnomad4 NFE exome

AF:

0.00569

Gnomad4 OTH exome

AF:

0.00413

GnomAD4 genome

AF:

0.00272

AC:

414

AN:

152342

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00489

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00192

Hom.:

Bravo

AF:

0.00266

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2015

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

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over