19-11021639-G-A

Variant names:

• chr19-11021639-G-A
• rs75904516
• NM_001387283.1:c.2617-86G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001387283.1(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_001387283.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.54
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.2617-86G>A		intron	N/A	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.2617-86G>A		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.2617-86G>A		intron	N/A	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.2617-86G>A		intron	N/A	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.2617-86G>A		intron	N/A	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.2617-86G>A		intron	N/A	ENSP00000493975.1

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

GnomAD2 exomes AF: 0.0290 AC: 4290 AN: 148064 AF XY: 0.0320

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 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

African (AFR) AF: 0.174 AC: 5376 AN: 30888

American (AMR) AF: 0.00828 AC: 296 AN: 35728

Ashkenazi Jewish (ASJ) AF: 0.000640 AC: 16 AN: 24982

East Asian (EAS) AF: 0.0163 AC: 581 AN: 35616

South Asian (SAS) AF: 0.0991 AC: 7748 AN: 78182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41866

Middle Eastern (MID) AF: 0.0168 AC: 95 AN: 5648

European-Non Finnish (NFE) AF: 0.000727 AC: 762 AN: 1048358

Other (OTH) AF: 0.0210 AC: 1195 AN: 56802

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

African (AFR) AF: 0.161 AC: 6706 AN: 41552

American (AMR) AF: 0.0142 AC: 218 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5188

South Asian (SAS) AF: 0.111 AC: 537 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68030

Other (OTH) AF: 0.0341 AC: 72 AN: 2114

Alfa AF: 0.0575 Hom.: 180

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327)

Hereditary cancer-predisposing syndrome Benign:1

May 20, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.24
DANN	Benign	0.94
PhyloP100		-1.5
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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