15-75349341-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PVS1_StrongPP3BP6_Very_StrongBS2

The NM_024608.4(NEIL1):c.434+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,600,384 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 33)

Exomes 𝑓: 0.011 ( 107 hom. )

Consequence

NEIL1
NM_024608.4 splice_donor, intron

Scores

Splicing: ADA: 0.9918

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.33

Variant links:

Genes affected

NEIL1 (HGNC:18448): (nei like DNA glycosylase 1) This gene is a member of the Nei endonuclease VIII-like gene family which encodes DNA glycosylases. The encoded enzyme participates in the DNA repair pathway by initiating base excision repair by removing damaged bases, primarily oxidized pyrimidines. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

NEIL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.3887468 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 16, new splice context is: cagGTgtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP3

Multiple lines of computational evidence support a deleterious effect 5: BayesDel_noAF, Cadd, dbscSNV1_ADA, max_spliceai, Eigen [when BayesDel_addAF, dbscSNV1_RF, MutationTaster was below the threshold]

BP6

Variant 15-75349341-T-C is Benign according to our data. Variant chr15-75349341-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 790285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEIL1	NM_024608.4 link	c.434+2T>C		splice_donor_variant, intron_variant	Intron 2 of 9	ENST00000355059.9	NP_078884.2	Q96FI4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEIL1	ENST00000355059.9 link	c.434+2T>C		splice_donor_variant, intron_variant	Intron 2 of 9	2	NM_024608.4	ENSP00000347170.4		Q96FI4

Frequencies

GnomAD3 genomes

AF:

0.00693

AC:

1055

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00716

AC:

1689

AN:

235788

Hom.:

AF XY:

0.00760

AC XY:

981

AN XY:

129088

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00546

Gnomad ASJ exome

AF:

0.00165

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00133

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0107

AC:

15525

AN:

1448096

Hom.:

107

Cov.:

AF XY:

0.0106

AC XY:

7632

AN XY:

719006

show subpopulations

Gnomad4 AFR exome

AF:

0.00148

Gnomad4 AMR exome

AF:

0.00558

Gnomad4 ASJ exome

AF:

0.00275

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00220

Gnomad4 NFE exome

AF:

0.0130

Gnomad4 OTH exome

AF:

0.00956

GnomAD4 genome

AF:

0.00693

AC:

1055

AN:

152288

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

465

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00516

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.00725

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00164

AC:

ESP6500EA

AF:

0.0126

AC:

105

ExAC

AF:

0.00681

AC:

821

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEIL1: BS1, BS2 -

Apr 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25525159, 18515411, 26662719) -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.92

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.57

Position offset: 14

DS_DL_spliceai

0.97

Position offset: -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