22-23834171-G-A

Variant names:

• chr22-23834171-G-A
• rs780103418
• NM_003073.5:c.1149G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003073.5(SMARCB1):​c.1149G>A​(p.Pro383Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 1,439,958 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P383P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 22-23834171-G-A is Benign according to our data. Variant chr22-23834171-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 410707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	NM_003073.5	MANE Select	c.1149G>A	p.Pro383Pro	synonymous	Exon 9 of 9	NP_003064.2
	SMARCB1	NM_001362877.2		c.1203G>A	p.Pro401Pro	synonymous	Exon 9 of 9	NP_001349806.1
	SMARCB1	NM_001317946.2		c.1176G>A	p.Pro392Pro	synonymous	Exon 9 of 9	NP_001304875.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	ENST00000644036.2	MANE Select	c.1149G>A	p.Pro383Pro	synonymous	Exon 9 of 9	ENSP00000494049.2
	SMARCB1	ENST00000407422.8	TSL:1	c.1122G>A	p.Pro374Pro	synonymous	Exon 9 of 9	ENSP00000383984.3
	SMARCB1	ENST00000263121.12	TSL:1	c.1011G>A	p.Pro337Pro	synonymous	Exon 8 of 8	ENSP00000263121.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000473 AC: 1 AN: 211458 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000833 AC: 12 AN: 1439958 Hom.: 0 Cov.: 33 AF XY: 0.0000112 AC XY: 8 AN XY: 714396

African (AFR) AF: 0.0000305 AC: 1 AN: 32782

American (AMR) AF: 0.00 AC: 0 AN: 42610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 38278

South Asian (SAS) AF: 0.0000363 AC: 3 AN: 82630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000635 AC: 7 AN: 1101674

Other (OTH) AF: 0.0000168 AC: 1 AN: 59464

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.0
DANN	Benign	0.89
PhyloP100		-1.2

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: rs780103418; hg19: chr22-24176358;