chr22-23816078-C-G

Variant names:

• chr22-23816078-C-G
• rs738799
• NM_003073.5:c.629-692C>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.629-692C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 153,246 control chromosomes in the GnomAD database, including 21,825 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 0.51 (21593 hom., cov: 31)
  • Exomes 𝑓: 0.57 (232 hom.)
• Consequence: SMARCB1 NM_003073.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290
• Publications: 5 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.629-692C>G		intron_variant	Intron 5 of 8	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.683-692C>G		intron_variant	Intron 5 of 8		NP_001349806.1
SMARCB1	NM_001317946.2	c.656-692C>G		intron_variant	Intron 5 of 8		NP_001304875.1
SMARCB1	NM_001007468.3	c.602-692C>G		intron_variant	Intron 5 of 8		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.629-692C>G		intron_variant	Intron 5 of 8		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76902 AN: 151846 Hom.: 21597 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.543

GnomAD4 exome AF: 0.572 AC: 733 AN: 1282 Hom.: 232 Cov.: 0 AF XY: 0.594 AC XY: 392 AN XY: 660

African (AFR) AF: 0.300 AC: 3 AN: 10

American (AMR) AF: 0.472 AC: 101 AN: 214

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.364 AC: 8 AN: 22

South Asian (SAS) AF: 0.660 AC: 33 AN: 50

European-Finnish (FIN) AF: 0.611 AC: 11 AN: 18

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.600 AC: 554 AN: 924

Other (OTH) AF: 0.523 AC: 23 AN: 44

GnomAD4 genome AF: 0.506 AC: 76895 AN: 151964 Hom.: 21593 Cov.: 31 AF XY: 0.508 AC XY: 37719 AN XY: 74270

African (AFR) AF: 0.248 AC: 10270 AN: 41432

American (AMR) AF: 0.603 AC: 9213 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2267 AN: 3470

East Asian (EAS) AF: 0.429 AC: 2216 AN: 5170

South Asian (SAS) AF: 0.637 AC: 3064 AN: 4812

European-Finnish (FIN) AF: 0.554 AC: 5841 AN: 10542

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42181 AN: 67950

Other (OTH) AF: 0.536 AC: 1133 AN: 2112

Alfa AF: 0.562 Hom.: 3154

Bravo AF: 0.492

Asia WGS AF: 0.490 AC: 1707 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.7
DANN	Benign	0.72
PhyloP100		0.029
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: rs738799; hg19: chr22-24158265;