rs922052006

Positions:

• chr22-23791831-G-A
• chr22-23791831-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1 PP2 BP4 BP6 BS1 BS2

The NM_003073.5(SMARCB1):​c.169G>A​(p.Val57Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,461,540 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V57A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.90

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 Benign. Variant got -7 ACMG points.

• PM1: In a region_of_interest DNA-binding (size 112) in uniprot entity SNF5_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_003073.5
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33929247).
• BP6: Variant 22-23791831-G-A is Benign according to our data. Variant chr22-23791831-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532973.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000369 (54/1461540) while in subpopulation NFE AF= 0.000045 (50/1111712). AF 95% confidence interval is 0.0000346. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.169G>A	p.Val57Met	missense_variant	2/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.169G>A	p.Val57Met	missense_variant	2/9
SMARCB1	NM_001317946.2	c.169G>A	p.Val57Met	missense_variant	2/9
SMARCB1	NM_001007468.3	c.169G>A	p.Val57Met	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.169G>A	p.Val57Met	missense_variant	2/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251492 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727106

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: 0.0000450

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 20, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 57 of the SMARCB1 protein (p.Val57Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532973). 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. 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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;T;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;.;.;.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.46	N;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.0	N;.;N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.11	T;.;T;T;T;T
Sift4G	Benign	0.15	T;.;T;T;T;T
Polyphen		0.017, 0.043, 0.84	.;B;B;.;.;P
Vest4		0.42
MutPred		0.19		Loss of ubiquitination at K61 (P = 0.0768);Loss of ubiquitination at K61 (P = 0.0768);Loss of ubiquitination at K61 (P = 0.0768);Loss of ubiquitination at K61 (P = 0.0768);Loss of ubiquitination at K61 (P = 0.0768);Loss of ubiquitination at K61 (P = 0.0768);
MVP		0.75
MPC		1.4
ClinPred		0.56	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.29
gMVP		0.71

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: rs922052006; hg19: chr22-24134018;