16-2047750-C-T

Position:

chr16-2047750-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002528.7(NTHL1):c.74G>A(p.Arg25Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,586,744 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 17 hom. )

Consequence

NTHL1
NM_002528.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.277

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037429929).

BP6

Variant 16-2047750-C-T is Benign according to our data. Variant chr16-2047750-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 708448.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000427 (65/152340) while in subpopulation EAS AF= 0.00695 (36/5180). AF 95% confidence interval is 0.00516. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTHL1	NM_002528.7 link	c.74G>A	p.Arg25Lys	missense_variant	1/6	ENST00000651570.2	NP_002519.2	P78549-2E5KTI5
NTHL1	NM_001318193.2 link	c.74G>A	p.Arg25Lys	missense_variant	1/5		NP_001305122.2	P78549
NTHL1	NM_001318194.2 link	c.-105G>A		5_prime_UTR_variant	1/6		NP_001305123.1	P78549
NTHL1	XM_047434171.1 link	c.-231G>A		5_prime_UTR_variant	1/6		XP_047290127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTHL1	ENST00000651570.2 link	c.74G>A	p.Arg25Lys	missense_variant	1/6		NM_002528.7	ENSP00000498421.1		P78549-2

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000478

AC:

AN:

198628

Hom.:

AF XY:

0.000461

AC XY:

AN XY:

110610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00328

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000576

Gnomad OTH exome

AF:

0.000196

GnomAD4 exome

AF:

0.000581

AC:

833

AN:

1434404

Hom.:

Cov.:

AF XY:

0.000574

AC XY:

409

AN XY:

712646

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.0178

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000226

Gnomad4 OTH exome

AF:

0.000386

GnomAD4 genome

AF:

0.000427

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00695

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000472

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.000389

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	TSC2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2025	Published functional studies demonstrate this variant induces cellular transformation but does not impact cellular localization or enzymatic functions of NTHL1 (PMID: 32595826); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (PMID: 33980861); This variant is associated with the following publications: (PMID: 33087284, 26400813, 21167187, 34363023, 32595826, 33980861) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 25, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

NTHL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2021

This variant is classified as likely 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.11

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.15

M_CAP

Benign

0.0040

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.21

REVEL

Benign

0.040

Sift

Benign

1.0

Sift4G

Benign

0.95

Polyphen

0.0

Vest4

0.14

MVP

0.072

MPC

0.063

ClinPred

0.0087

GERP RS

1.2

Varity_R

0.16

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over