rs12232780

Variant names:

• chr19-11021404-G-A
• rs12232780
• NM_001387283.1:c.2617-321G>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.2617-321G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 440,446 control chromosomes in the GnomAD database, including 18,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4941 hom., cov: 33)
  • Exomes 𝑓: 0.30 (13584 hom.)
• Consequence: SMARCA4 NM_003072.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.325

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=-0.95).
• BP6: Variant 19-11021404-G-A is Benign according to our data. Variant chr19-11021404-G-A is described in ClinVar as [Benign]. Clinvar id is 1249450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2617-321G>A		intron_variant	Intron 18 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2617-321G>A		intron_variant	Intron 18 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2617-321G>A		intron_variant	Intron 18 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2617-321G>A		intron_variant	Intron 18 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2617-321G>A		intron_variant	Intron 18 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2617-321G>A		intron_variant	Intron 19 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2617-321G>A		intron_variant	Intron 18 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2617-321G>A		intron_variant	Intron 18 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2617-321G>A		intron_variant	Intron 19 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2029-321G>A		intron_variant	Intron 15 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1261-321G>A		intron_variant	Intron 11 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1342-321G>A		intron_variant	Intron 11 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1102-321G>A		intron_variant	Intron 10 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.970-321G>A		intron_variant	Intron 9 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36013 AN: 152066 Hom.: 4943 Cov.: 33

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.297 AC: 85670 AN: 288262 Hom.: 13584 Cov.: 0 AF XY: 0.305 AC XY: 46840 AN XY: 153512

Gnomad4 AFR exome AF: 0.0840

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.340

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.237 AC: 36013 AN: 152184 Hom.: 4941 Cov.: 33 AF XY: 0.241 AC XY: 17900 AN XY: 74402

Gnomad4 AFR AF: 0.0916

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.346

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.244

Alfa AF: 0.267 Hom.: 1566

Bravo AF: 0.218

Asia WGS AF: 0.266 AC: 928 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12232780; hg19: chr19-11132080;