NM_003073.5:c.500+305C>A

Variant names:

• chr22-23801386-C-A
• rs35502837
• NM_003073.5:c.500+305C>A

Variant summary

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

The NM_003073.5(SMARCB1):​c.500+305C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 667,950 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (39 hom., cov: 32)
  • Exomes 𝑓: 0.027 (249 hom.)
• Consequence: SMARCB1 NM_003073.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.06
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-23801386-C-A is Benign according to our data. Variant chr22-23801386-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 133393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0209 (3181/152324) while in subpopulation NFE AF = 0.0294 (2002/68024). AF 95% confidence interval is 0.0284. There are 39 homozygotes in GnomAd4. There are 1613 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3181 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	NM_003073.5	MANE Select	c.500+305C>A		intron	N/A	NP_003064.2
	SMARCB1	NM_001362877.2		c.554+251C>A		intron	N/A	NP_001349806.1
	SMARCB1	NM_001317946.2		c.527+251C>A		intron	N/A	NP_001304875.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	ENST00000644036.2	MANE Select	c.500+305C>A		intron	N/A	ENSP00000494049.2
	SMARCB1	ENST00000407422.8	TSL:1	c.473+305C>A		intron	N/A	ENSP00000383984.3
	SMARCB1	ENST00000263121.12	TSL:1	c.363-1909C>A		intron	N/A	ENSP00000263121.8

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3182 AN: 152206 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0224

GnomAD2 exomes AF: 0.0231 AC: 2963 AN: 128418 AF XY: 0.0244

Gnomad AFR exome AF: 0.00473

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0374

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0268 AC: 13835 AN: 515626 Hom.: 249 Cov.: 0 AF XY: 0.0275 AC XY: 7691 AN XY: 279670

African (AFR) AF: 0.00540 AC: 82 AN: 15174

American (AMR) AF: 0.0124 AC: 416 AN: 33504

Ashkenazi Jewish (ASJ) AF: 0.0390 AC: 743 AN: 19054

East Asian (EAS) AF: 0.00 AC: 0 AN: 29302

South Asian (SAS) AF: 0.0285 AC: 1755 AN: 61564

European-Finnish (FIN) AF: 0.0379 AC: 1112 AN: 29372

Middle Eastern (MID) AF: 0.0354 AC: 138 AN: 3900

European-Non Finnish (NFE) AF: 0.0300 AC: 8845 AN: 295164

Other (OTH) AF: 0.0260 AC: 744 AN: 28592

GnomAD4 genome AF: 0.0209 AC: 3181 AN: 152324 Hom.: 39 Cov.: 32 AF XY: 0.0217 AC XY: 1613 AN XY: 74484

African (AFR) AF: 0.00503 AC: 209 AN: 41578

American (AMR) AF: 0.0156 AC: 238 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0290 AC: 140 AN: 4828

European-Finnish (FIN) AF: 0.0386 AC: 410 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0294 AC: 2002 AN: 68024

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0267 Hom.: 97

Bravo AF: 0.0183

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.28
DANN	Benign	0.56
PhyloP100		-1.1
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: rs35502837; hg19: chr22-24143573; COSMIC: COSV54093735; COSMIC: COSV54093735;