rs150766139

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_002528.7(NTHL1):c.244C>T(p.Gln82*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q82Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 1 hom. )

Consequence

NTHL1
NM_002528.7 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:36U:1O:1

Conservation

PhyloP100: 0.670

Publications

64 publications found

Variant links:

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]

NTHL1 Gene-Disease associations (from GenCC):

familial adenomatous polyposis 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
NTHL1-deficiency tumor predisposition syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
breast cancer
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
meningioma
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NTHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-2046238-G-A is Pathogenic according to our data. Variant chr16-2046238-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192319.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTHL1	NM_002528.7	MANE Select	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 6	NP_002519.2	P78549-2
NTHL1	NM_001318193.2		c.244C>T	p.Gln82*	stop_gained	Exon 2 of 5	NP_001305122.2
NTHL1	NM_001318194.2		c.24+42C>T		intron	N/A	NP_001305123.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTHL1	ENST00000651570.2	MANE Select	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 6	ENSP00000498421.1	P78549-2
NTHL1	ENST00000219066.5	TSL:1	c.268C>T	p.Gln90*	stop_gained	Exon 2 of 6	ENSP00000219066.1	P78549-1
NTHL1	ENST00000925707.1		c.244C>T	p.Gln82*	stop_gained	Exon 2 of 6	ENSP00000595766.1

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

204

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00141

AC:

354

AN:

250862

AF XY:

0.00143

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00375

Gnomad NFE exome

AF:

0.00199

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00162

AC:

2364

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1172

AN XY:

726740

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000738

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00476

AC:

250

AN:

52514

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00176

AC:

1960

AN:

1111988

Other (OTH)

AF:

0.00134

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00134

AC:

204

AN:

152256

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41544

American (AMR)

AF:

0.00111

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00396

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00146

Hom.:

Bravo

AF:

0.000986

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00153

AC:

186

EpiCase

AF:

0.00224

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial adenomatous polyposis 3 (16)

not provided (14)

Hereditary cancer-predisposing syndrome (5)

Colorectal cancer (1)

Inherited polyposis and early onset colorectal cancer - germline testing (1)

NTHL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.15

PhyloP100

0.67

Vest4

0.40

GERP RS

4.8

PromoterAI

-0.0078

Neutral

(source)

Mutation Taster

=11/189

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over