19-11021639-G-A

Position:

• chr19-11021639-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003072.5(SMARCA4):​c.2617-86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,510,384 control chromosomes in the GnomAD database, including 1,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (628 hom., cov: 33)
  • Exomes 𝑓: 0.012 (1022 hom.)
• Consequence: SMARCA4 NM_003072.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.54

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-11021639-G-A is Benign according to our data. Variant chr19-11021639-G-A is described in ClinVar as [Benign]. Clinvar id is 133384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2617-86G>A		intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2617-86G>A		intron_variant		ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2617-86G>A		intron_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2617-86G>A		intron_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2617-86G>A		intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2617-86G>A		intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2617-86G>A		intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2617-86G>A		intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2617-86G>A		intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2029-86G>A		intron_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1261-86G>A		intron_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1342-86G>A		intron_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1102-86G>A		intron_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.970-86G>A		intron_variant				ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7736 AN: 152196 Hom.: 620 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0290 AC: 4290 AN: 148064 Hom.: 259 AF XY: 0.0320 AC XY: 2545 AN XY: 79468

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.00689

Gnomad ASJ exome AF: 0.000591

Gnomad EAS exome AF: 0.0222

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0118 AC: 16069 AN: 1358070 Hom.: 1022 Cov.: 24 AF XY: 0.0140 AC XY: 9410 AN XY: 672334

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.00828

Gnomad4 ASJ exome AF: 0.000640

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.0991

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000727

Gnomad4 OTH exome AF: 0.0210

GnomAD4 genome AF: 0.0510 AC: 7770 AN: 152314 Hom.: 628 Cov.: 33 AF XY: 0.0513 AC XY: 3824 AN XY: 74482

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.00967 Hom.: 13

Bravo AF: 0.0540

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2015

This alteration is classified as 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. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.24
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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

LitVar

Other links and lift over

dbSNP: rs75904516; hg19: chr19-11132315; COSMIC: COSV60808626; COSMIC: COSV60808626;