rs2229354

Variant names:

• chr22-23825326-G-A
• rs2229354
• NM_003073.5:c.897G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-23825326-G-A
• chr22-23825326-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003073.5(SMARCB1):​c.897G>A​(p.Ser299Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,008 control chromosomes in the GnomAD database, including 10,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S299S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (880 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10101 hom.)
• Consequence: SMARCB1 NM_003073.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.33
• Publications: 37 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: ClinGen, Orphanet
• intellectual disability, autosomal dominant 15

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-23825326-G-A is Benign according to our data. Variant chr22-23825326-G-A is described in ClinVar as Benign. ClinVar VariationId is 126368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	NM_003073.5	MANE Select	c.897G>A	p.Ser299Ser	synonymous	Exon 7 of 9	NP_003064.2
	SMARCB1	NM_001362877.2		c.951G>A	p.Ser317Ser	synonymous	Exon 7 of 9	NP_001349806.1
	SMARCB1	NM_001317946.2		c.924G>A	p.Ser308Ser	synonymous	Exon 7 of 9	NP_001304875.1	G5E975

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	ENST00000644036.2	MANE Select	c.897G>A	p.Ser299Ser	synonymous	Exon 7 of 9	ENSP00000494049.2	Q12824-1
	SMARCB1	ENST00000407422.8	TSL:1	c.870G>A	p.Ser290Ser	synonymous	Exon 7 of 9	ENSP00000383984.3	Q12824-2
	SMARCB1	ENST00000263121.12	TSL:1	c.759G>A	p.Ser253Ser	synonymous	Exon 6 of 8	ENSP00000263121.8	A0A0G2JRV3

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16051 AN: 152170 Hom.: 880 Cov.: 33

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0884

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0750

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.112 AC: 28247 AN: 251442 AF XY: 0.116

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0777

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.114 AC: 166761 AN: 1461720 Hom.: 10101 Cov.: 32 AF XY: 0.116 AC XY: 84346 AN XY: 727164

African (AFR) AF: 0.0854 AC: 2859 AN: 33478

American (AMR) AF: 0.0787 AC: 3520 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2788 AN: 26134

East Asian (EAS) AF: 0.0460 AC: 1826 AN: 39698

South Asian (SAS) AF: 0.176 AC: 15171 AN: 86254

European-Finnish (FIN) AF: 0.128 AC: 6850 AN: 53418

Middle Eastern (MID) AF: 0.154 AC: 886 AN: 5768

European-Non Finnish (NFE) AF: 0.113 AC: 125780 AN: 1111866

Other (OTH) AF: 0.117 AC: 7081 AN: 60386

GnomAD4 genome AF: 0.105 AC: 16048 AN: 152288 Hom.: 880 Cov.: 33 AF XY: 0.106 AC XY: 7884 AN XY: 74464

African (AFR) AF: 0.0858 AC: 3567 AN: 41554

American (AMR) AF: 0.0884 AC: 1352 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3472

East Asian (EAS) AF: 0.0747 AC: 387 AN: 5178

South Asian (SAS) AF: 0.169 AC: 817 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1379 AN: 10628

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7799 AN: 68012

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.103 Hom.: 795

Bravo AF: 0.0997

Asia WGS AF: 0.106 AC: 367 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.115

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Rhabdoid tumor predisposition syndrome 1 (2)
-	-	2	SMARCB1-related schwannomatosis (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.50
PhyloP100		-3.3
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: rs2229354; hg19: chr22-24167513; COSMIC: COSV54093776;