rs749030456

Positions:

• chr9-132928809-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5 PP2 BP6 BS2

The NM_000368.5(TSC1):​c.64C>T​(p.Arg22Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R22Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 2.63

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132928808-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
• BP6: Variant 9-132928809-G-A is Benign according to our data. Variant chr9-132928809-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417731.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.64C>T	p.Arg22Trp	missense_variant	3/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.64C>T	p.Arg22Trp	missense_variant	3/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.64C>T	p.Arg22Trp	missense_variant	4/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251306 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 2024	The p.R22W variant (also known as c.64C>T), located in coding exon 1 of the TSC1 gene, results from a C to T substitution at nucleotide position 64. The arginine at codon 22 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with core binding factor acute myeloid leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was also identified in 1/190 unrelated Chinese patients under the age of 45 who presented with renal tumors (Wu J et al. Cancer, 2019 04;125:1060-1069). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Isolated focal cortical dysplasia type II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 11, 2017

- -

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

May 20, 2021

The TSC1 c.64C>T (p.Arg22Trp) missense change has a maximum frequency of 0.011% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/17-17125860-G-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function. Functional assays indicate that this variant may disrupt the TSC1-TSC2 complex and activate the mTOR pathway (PMID: 28215400). This variant was identified as a low-level somatic mutation in the brain tissue of three individuals with focal cortical dysplasia (PMID: 28215400). To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.8	L;L;L;.;L;.;L;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.98	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.023	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Sift4G	Uncertain	0.013	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.98	D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.;.
Vest4		0.42
MutPred		0.63		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.71
MPC		1.2
ClinPred		0.62	D
GERP RS		3.2
Varity_R		0.038
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749030456; hg19: chr9-135804196; COSMIC: COSV53770666;