rs118203426

chr9-132921429-A-Cchr9-132921429-A-Gchr9-132921429-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000368.5(TSC1):c.671T>G(p.Met224Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M224L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TSC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 9-132921429-A-C is Pathogenic according to our data. Variant chr9-132921429-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5104.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132921429-A-C is described in Lovd as [Pathogenic]. Variant chr9-132921429-A-C is described in Lovd as [Pathogenic]. Variant chr9-132921429-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.671T>G	p.Met224Arg	missense_variant	8/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.671T>G	p.Met224Arg	missense_variant	8/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2020	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect TSC1 protein function (PMID: 18830229, 21309039, 20547222). This variant has been observed in individuals and families affected with tuberous sclerosis complex (PMID: 18830229, Invitae). ClinVar contains an entry for this variant (Variation ID: 5104). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 224 of the TSC1 protein (p.Met224Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.3	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.1	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.98	D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.
Vest4		0.85
MutPred		0.91		Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);
MVP		0.93
MPC		1.7
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203426; hg19: chr9-135796816;