rs2233518

Positions:

• chr16-2046383-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.802

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). 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 id is 1284832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2046383-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTHL1	NM_002528.7	c.116-17C>T		intron_variant		ENST00000651570.2	NP_002519.2
NTHL1	XM_047434171.1	c.-181C>T		5_prime_UTR_variant	2/6		XP_047290127.1
NTHL1	NM_001318193.2	c.116-17C>T		intron_variant			NP_001305122.2
NTHL1	NM_001318194.2	c.-63-17C>T		intron_variant			NP_001305123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTHL1	ENST00000651570.2	c.116-17C>T		intron_variant			NM_002528.7	ENSP00000498421.1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1488 AN: 152182 Hom.: 21 Cov.: 32

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

GnomAD3 exomes AF: 0.00267 AC: 656 AN: 245272 Hom.: 10 AF XY: 0.00193 AC XY: 257 AN XY: 133456

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 SAS exome AF: 0.000132

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.: 19 Cov.: 31 AF XY: 0.000906 AC XY: 650 AN XY: 717606

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00980 AC: 1493 AN: 152300 Hom.: 21 Cov.: 32 AF XY: 0.00969 AC XY: 722 AN XY: 74476

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00519 Hom.: 4

Bravo AF: 0.0111

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

NTHL1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

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
DANN	Benign	0.81
BranchPoint Hunter		2.0

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

LitVar

Other links and lift over

dbSNP: rs2233518; hg19: chr16-2096384;