22-23787259-C-T

Variant names:

• chr22-23787259-C-T
• rs761868468
• NM_003073.5:c.90C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6 BP7 BS2

The NM_003073.5(SMARCB1):​c.90C>T​(p.Ser30Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,435,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S30S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.868
• Publications: 1 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, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp, G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 22-23787259-C-T is Benign according to our data. Variant chr22-23787259-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532978.
• BP7: Synonymous conserved (PhyloP=-0.868 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 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.90C>T	p.Ser30Ser	synonymous	Exon 1 of 9	NP_003064.2
	SMARCB1	NM_001362877.2		c.90C>T	p.Ser30Ser	synonymous	Exon 1 of 9	NP_001349806.1
	SMARCB1	NM_001317946.2		c.90C>T	p.Ser30Ser	synonymous	Exon 1 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.90C>T	p.Ser30Ser	synonymous	Exon 1 of 9	ENSP00000494049.2	Q12824-1
	SMARCB1	ENST00000407422.8	TSL:1	c.90C>T	p.Ser30Ser	synonymous	Exon 1 of 9	ENSP00000383984.3	Q12824-2
	SMARCB1	ENST00000263121.12	TSL:1	c.90C>T	p.Ser30Ser	synonymous	Exon 1 of 8	ENSP00000263121.8	A0A0G2JRV3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1435688 Hom.: 0 Cov.: 27 AF XY: 0.00000280 AC XY: 2 AN XY: 715352

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.00 AC: 0 AN: 43568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 38100

South Asian (SAS) AF: 0.00 AC: 0 AN: 84582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1094450

Other (OTH) AF: 0.0000337 AC: 2 AN: 59432

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	SMARCB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		-0.87
PromoterAI		0.036	Neutral

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: rs761868468; hg19: chr22-24129446;