22-23787175-G-A

Position:

• chr22-23787175-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_003073.5(SMARCB1):​c.6G>A​(p.Met2Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest DNA-binding (size 112) in uniprot entity SNF5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCB1. . Gene score misZ 3.6016 (greater than the threshold 3.09). Trascript score misZ 4.8554 (greater than threshold 3.09). GenCC has associacion of gene with schwannomatosis 1, familial multiple meningioma, rhabdoid tumor predisposition syndrome 1, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 15, familial rhabdoid tumor, schwannomatosis, Coffin-Siris syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.6G>A	p.Met2Ile	missense_variant	1/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.6G>A	p.Met2Ile	missense_variant	1/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.6G>A	p.Met2Ile	missense_variant	1/9		NP_001304875.1
SMARCB1	NM_001007468.3	c.6G>A	p.Met2Ile	missense_variant	1/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.6G>A	p.Met2Ile	missense_variant	1/9		NM_003073.5	ENSP00000494049	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454586 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723878

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 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. This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2 of the SMARCB1 protein (p.Met2Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	.;T;T;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0073
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	.;.;.;.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.69	N;N;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.68	N;.;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.24	T;.;T;T;T;T
Sift4G	Benign	0.50	T;.;T;T;T;T
Polyphen		0.0, 0.013, 0.53	.;B;B;.;.;P
Vest4		0.63
MutPred		0.28		Gain of catalytic residue at M2 (P = 0.0315);Gain of catalytic residue at M2 (P = 0.0315);Gain of catalytic residue at M2 (P = 0.0315);Gain of catalytic residue at M2 (P = 0.0315);Gain of catalytic residue at M2 (P = 0.0315);Gain of catalytic residue at M2 (P = 0.0315);
MVP		0.90
MPC		1.4
ClinPred		0.81	D
GERP RS		3.5
Varity_R		0.32
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24129362;