rs762676176

chr22-23787248-A-Cchr22-23787248-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_003073.5(SMARCB1):c.79A>C(p.Met27Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M27R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest DNA-binding (size 112) in uniprot entity SNF5_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23787249-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 838596.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, SMARCB1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.79A>C	p.Met27Leu	missense_variant	1/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.79A>C	p.Met27Leu	missense_variant	1/9
SMARCB1	NM_001317946.2	c.79A>C	p.Met27Leu	missense_variant	1/9
SMARCB1	NM_001007468.3	c.79A>C	p.Met27Leu	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.79A>C	p.Met27Leu	missense_variant	1/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 244006 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132852

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449104 Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3 AN XY: 721572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 13, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 464339). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. This variant is present in population databases (rs762676176, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 27 of the SMARCB1 protein (p.Met27Leu). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The p.M27L variant (also known as c.79A>C), located in coding exon 1 of the SMARCB1 gene, results from an A to C substitution at nucleotide position 79. The methionine at codon 27 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Missense and in-frame variants in SMARCB1 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Eaton KW et al. Pediatr Blood Cancer. 2011 Jan;56(1):7-15). Based on the supporting evidence, the association of this alteration with SMARCB1-related tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Benign	0.87
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.052
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.9	L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.46	T;.;T;T;T;T
Sift4G	Benign	1.0	T;.;T;T;T;T
Polyphen		0.10, 0.0010, 0.0	.;B;B;.;.;B
Vest4		0.64
MutPred		0.34		Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);
MVP		0.78
MPC		1.2
ClinPred		0.95	D
GERP RS		2.4
Varity_R		0.62
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs762676176; hg19: chr22-24129435;