rs2233518

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002528.7(NTHL1):c.116-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,598,958 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0098 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 19 hom. )

Consequence

NTHL1
NM_002528.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.802

Publications

1 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, 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: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 16-2046383-G-A is Benign according to our data. Variant chr16-2046383-G-A is described in ClinVar as Benign. ClinVar VariationId is 1284832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0098 (1493/152300) while in subpopulation AFR AF = 0.0341 (1417/41544). AF 95% confidence interval is 0.0326. There are 21 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NTHL1	NM_002528.7 link	c.116-17C>T	intron_variant	Intron 1 of 5	ENST00000651570.2	NP_002519.2	P78549-2E5KTI5
NTHL1	XM_047434171.1 link	c.-181C>T	5_prime_UTR_variant	Exon 2 of 6		XP_047290127.1
NTHL1	NM_001318193.2 link	c.116-17C>T	intron_variant	Intron 1 of 4		NP_001305122.2	P78549
NTHL1	NM_001318194.2 link	c.-63-17C>T	intron_variant	Intron 1 of 5		NP_001305123.1	P78549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTHL1	ENST00000651570.2 link	c.116-17C>T		intron_variant	Intron 1 of 5		NM_002528.7	ENSP00000498421.1		P78549-2

Frequencies

GnomAD3 genomes

AF:

0.00978

AC:

1488

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00267

AC:

656

AN:

245272

AF XY:

0.00193

show subpopulations

Gnomad AFR exome

AF:

0.0357

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.00105

AC:

1516

AN:

1446658

Hom.:

Cov.:

AF XY:

0.000906

AC XY:

650

AN XY:

717606

show subpopulations

African (AFR)

AF:

0.0347

AC:

1153

AN:

33232

American (AMR)

AF:

0.00173

AC:

AN:

44438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39436

South Asian (SAS)

AF:

0.000140

AC:

AN:

85962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49384

Middle Eastern (MID)

AF:

0.00158

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.000131

AC:

144

AN:

1102718

Other (OTH)

AF:

0.00202

AC:

121

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00980

AC:

1493

AN:

152300

Hom.:

Cov.:

AF XY:

0.00969

AC XY:

722

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0341

AC:

1417

AN:

41544

American (AMR)

AF:

0.00327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00515

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial adenomatous polyposis 3

Benign:1

Dec 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NTHL1-related disorder

Benign:1

Nov 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.1

(source)

DANN

Benign

0.81

PhyloP100

-0.80

BranchPoint Hunter

2.0

PromoterAI

0.0024

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over