rs6003904

Variant names:

• chr22-23831207-A-G
• rs6003904
• NM_003073.5:c.987-2365A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003073.5(SMARCB1):​c.987-2365A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,048 control chromosomes in the GnomAD database, including 5,732 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5732 hom., cov: 32)
• Consequence: SMARCB1 NM_003073.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• Publications: 14 publications found

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schwannomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003073.5. 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
	SMARCB1	NM_003073.5	MANE Select	c.987-2365A>G		intron	N/A	NP_003064.2
	SMARCB1	NM_001362877.2		c.1041-2365A>G		intron	N/A	NP_001349806.1
	SMARCB1	NM_001317946.2		c.1014-2365A>G		intron	N/A	NP_001304875.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	ENST00000644036.2	MANE Select	c.987-2365A>G		intron	N/A	ENSP00000494049.2
	SMARCB1	ENST00000407422.8	TSL:1	c.960-2365A>G		intron	N/A	ENSP00000383984.3
	SMARCB1	ENST00000263121.12	TSL:1	c.849-2365A>G		intron	N/A	ENSP00000263121.8

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34679 AN: 151930 Hom.: 5715 Cov.: 32

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34727 AN: 152048 Hom.: 5732 Cov.: 32 AF XY: 0.226 AC XY: 16826 AN XY: 74358

African (AFR) AF: 0.467 AC: 19323 AN: 41416

American (AMR) AF: 0.151 AC: 2300 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 543 AN: 3466

East Asian (EAS) AF: 0.100 AC: 520 AN: 5184

South Asian (SAS) AF: 0.277 AC: 1339 AN: 4826

European-Finnish (FIN) AF: 0.132 AC: 1398 AN: 10586

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8622 AN: 67974

Other (OTH) AF: 0.214 AC: 452 AN: 2114

Alfa AF: 0.205 Hom.: 868

Bravo AF: 0.236

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0070
DANN	Benign	0.60
PhyloP100		-1.7
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: rs6003904; hg19: chr22-24173394;