rs2516740

Variant names:

• chr16-2047109-A-C
• rs2516740
• NM_002528.7:c.115+600T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002528.7(NTHL1):​c.115+600T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 153,120 control chromosomes in the GnomAD database, including 8,920 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8905 hom., cov: 33)
  • Exomes 𝑓: 0.16 (15 hom.)
• Consequence: NTHL1 NM_002528.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 10 publications found

Genes affected

NTHL1 (HGNC:8028): (nth like DNA glycosylase 1) The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• lymphangioleiomyomatosis

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002528.7. 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
	NTHL1	NM_002528.7	MANE Select	c.115+600T>G		intron	N/A	NP_002519.2	P78549-2
	NTHL1	NM_001318193.2		c.115+600T>G		intron	N/A	NP_001305122.2
	NTHL1	NM_001318194.2		c.-64+600T>G		intron	N/A	NP_001305123.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTHL1	ENST00000651570.2	MANE Select	c.115+600T>G		intron	N/A	ENSP00000498421.1	P78549-2
	NTHL1	ENST00000219066.5	TSL:1	c.139+600T>G		intron	N/A	ENSP00000219066.1	P78549-1
	NTHL1	ENST00000925707.1		c.115+600T>G		intron	N/A	ENSP00000595766.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46316 AN: 151984 Hom.: 8873 Cov.: 33

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.295

GnomAD4 exome AF: 0.159 AC: 162 AN: 1018 Hom.: 15 Cov.: 0 AF XY: 0.147 AC XY: 85 AN XY: 578

African (AFR) AF: 0.500 AC: 3 AN: 6

American (AMR) AF: 0.0758 AC: 5 AN: 66

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 1 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.0942 AC: 13 AN: 138

European-Finnish (FIN) AF: 0.167 AC: 4 AN: 24

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.181 AC: 132 AN: 730

Other (OTH) AF: 0.133 AC: 4 AN: 30

GnomAD4 genome AF: 0.305 AC: 46397 AN: 152102 Hom.: 8905 Cov.: 33 AF XY: 0.301 AC XY: 22381 AN XY: 74346

African (AFR) AF: 0.542 AC: 22468 AN: 41456

American (AMR) AF: 0.241 AC: 3682 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 978 AN: 3470

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5174

South Asian (SAS) AF: 0.125 AC: 604 AN: 4832

European-Finnish (FIN) AF: 0.243 AC: 2577 AN: 10588

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15039 AN: 67978

Other (OTH) AF: 0.291 AC: 615 AN: 2110

Alfa AF: 0.243 Hom.: 2372

Bravo AF: 0.317

Asia WGS AF: 0.107 AC: 373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.7
DANN	Benign	0.43
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2516740; hg19: chr16-2097110;