rs748845915

Variant names:

• chr9-132897514-G-A
• rs748845915
• NM_000368.5:c.2722C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132897514-G-A
• chr9-132897514-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000368.5(TSC1):​c.2722C>T​(p.Arg908Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,599,794 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. R908Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.80
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 9-132897514-G-A is Benign according to our data. Variant chr9-132897514-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 486563.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2722C>T	p.Arg908Trp	missense	Exon 21 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.2722C>T	p.Arg908Trp	missense	Exon 21 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.2722C>T	p.Arg908Trp	missense	Exon 21 of 23	NP_001393522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2722C>T	p.Arg908Trp	missense	Exon 21 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2722C>T	p.Arg908Trp	missense	Exon 22 of 24	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2722C>T	p.Arg908Trp	missense	Exon 21 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes AF: 0.00000679 AC: 1 AN: 147208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251368 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1452586 Hom.: 0 Cov.: 37 AF XY: 0.0000166 AC XY: 12 AN XY: 722752

African (AFR) AF: 0.0000300 AC: 1 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25670

East Asian (EAS) AF: 0.00 AC: 0 AN: 38930

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1106140

Other (OTH) AF: 0.0000167 AC: 1 AN: 59774

GnomAD4 genome AF: 0.00000679 AC: 1 AN: 147208 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71294

African (AFR) AF: 0.00 AC: 0 AN: 40324

American (AMR) AF: 0.00 AC: 0 AN: 14332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 4752

South Asian (SAS) AF: 0.00 AC: 0 AN: 4424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67270

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.0000591 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Tuberous sclerosis 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.27		Loss of disorder (P = 0.0107)
MVP		0.98
MPC		1.4
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.48
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs748845915; hg19: chr9-135772901;