rs201665695

chr19-11059895-G-Achr19-11059895-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001387283.1(SMARCA4):c.4864+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,613,196 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0710

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-11059895-G-A is Benign according to our data. Variant chr19-11059895-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00186 (283/152266) while in subpopulation AFR AF= 0.00616 (256/41572). AF 95% confidence interval is 0.00554. There are 0 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 281 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.4864+10G>A		intron_variant		ENST00000646693.2
SMARCA4	NM_003072.5	c.4768+10G>A		intron_variant		ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000344626.10	c.4768+10G>A		intron_variant		1	NM_003072.5	P4
SMARCA4	ENST00000646693.2	c.4864+10G>A		intron_variant			NM_001387283.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000432 AC: 107 AN: 247510 Hom.: 0 AF XY: 0.000305 AC XY: 41 AN XY: 134240

Gnomad AFR exome AF: 0.00581

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1460930 Hom.: 3 Cov.: 32 AF XY: 0.000180 AC XY: 131 AN XY: 726782

Gnomad4 AFR exome AF: 0.00687

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74442

Gnomad4 AFR AF: 0.00616

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00232

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2018	- -

Intellectual disability, autosomal dominant 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 14, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.022
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs201665695; hg19: chr19-11170571;