NM_003073.5:c.501-466A>G

Variant names:

• chr22-23802829-A-G
• rs11703707
• NM_003073.5:c.501-466A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003073.5(SMARCB1):​c.501-466A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 299,720 control chromosomes in the GnomAD database, including 48 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 0.015 (25 hom., cov: 31)
  • Exomes 𝑓: 0.015 (23 hom.)
• Consequence: SMARCB1 NM_003073.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 2 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=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0147 (2229/152084) while in subpopulation NFE AF = 0.0228 (1548/67966). AF 95% confidence interval is 0.0218. There are 25 homozygotes in GnomAd4. There are 1066 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.501-466A>G		intron_variant	Intron 4 of 8	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.555-466A>G		intron_variant	Intron 4 of 8		NP_001349806.1
SMARCB1	NM_001317946.2	c.528-466A>G		intron_variant	Intron 4 of 8		NP_001304875.1
SMARCB1	NM_001007468.3	c.474-466A>G		intron_variant	Intron 4 of 8		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.501-466A>G		intron_variant	Intron 4 of 8		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2229 AN: 151966 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0155 AC: 2282 AN: 147636 Hom.: 23 Cov.: 0 AF XY: 0.0146 AC XY: 1157 AN XY: 79390

African (AFR) AF: 0.00306 AC: 14 AN: 4572

American (AMR) AF: 0.00832 AC: 52 AN: 6250

Ashkenazi Jewish (ASJ) AF: 0.00800 AC: 28 AN: 3500

East Asian (EAS) AF: 0.00 AC: 0 AN: 6296

South Asian (SAS) AF: 0.00743 AC: 201 AN: 27056

European-Finnish (FIN) AF: 0.0172 AC: 113 AN: 6560

Middle Eastern (MID) AF: 0.00190 AC: 1 AN: 526

European-Non Finnish (NFE) AF: 0.0207 AC: 1772 AN: 85596

Other (OTH) AF: 0.0139 AC: 101 AN: 7280

GnomAD4 genome AF: 0.0147 AC: 2229 AN: 152084 Hom.: 25 Cov.: 31 AF XY: 0.0143 AC XY: 1066 AN XY: 74348

African (AFR) AF: 0.00417 AC: 173 AN: 41468

American (AMR) AF: 0.0128 AC: 195 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4816

European-Finnish (FIN) AF: 0.0206 AC: 218 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1548 AN: 67966

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0198 Hom.: 42

Bravo AF: 0.0135

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.15
DANN	Benign	0.45
PhyloP100		-1.4
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: rs11703707; hg19: chr22-24145016;