chr19-10984387-T-C

Variant names:

• chr19-10984387-T-C
• rs112825147
• NM_001387283.1:c.222+14T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001387283.1(SMARCA4):​c.222+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,565,702 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.670
• Publications: 1 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=-0.89).
• BP6: Variant 19-10984387-T-C is Benign according to our data. Variant chr19-10984387-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328019.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 = 0.00536 (816/152322) while in subpopulation AFR AF = 0.0168 (699/41592). AF 95% confidence interval is 0.0158. There are 13 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.222+14T>C		intron_variant	Intron 2 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.222+14T>C		intron_variant	Intron 2 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.222+14T>C		intron_variant	Intron 2 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.222+14T>C		intron_variant	Intron 2 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.222+14T>C		intron_variant	Intron 2 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.222+14T>C		intron_variant	Intron 3 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.222+14T>C		intron_variant	Intron 2 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.222+14T>C		intron_variant	Intron 2 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.222+14T>C		intron_variant	Intron 3 of 34	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 798 AN: 152204 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00251 AC: 426 AN: 169396 AF XY: 0.00262

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.00313

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00111 AC: 1568 AN: 1413380 Hom.: 25 Cov.: 33 AF XY: 0.00120 AC XY: 837 AN XY: 698792

African (AFR) AF: 0.0177 AC: 565 AN: 32008

American (AMR) AF: 0.000994 AC: 38 AN: 38248

Ashkenazi Jewish (ASJ) AF: 0.00292 AC: 74 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 36654

South Asian (SAS) AF: 0.00493 AC: 398 AN: 80688

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49316

Middle Eastern (MID) AF: 0.00875 AC: 48 AN: 5486

European-Non Finnish (NFE) AF: 0.000256 AC: 278 AN: 1087166

Other (OTH) AF: 0.00284 AC: 166 AN: 58508

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152322 Hom.: 13 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74484

African (AFR) AF: 0.0168 AC: 699 AN: 41592

American (AMR) AF: 0.00229 AC: 35 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68004

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00419 Hom.: 2

Bravo AF: 0.00588

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 20, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Coffin-Siris syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.43
DANN	Benign	0.41
PhyloP100		-0.67
PromoterAI		0.0012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs112825147; hg19: chr19-11095063; COSMIC: COSV104418510;