rs5745908

chr15-75349341-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PVS1_Strong PP3 BP6_Very_Strong BS2

The NM_024608.4(NEIL1):c.434+2T>C variant causes a splice donor 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
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.33

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.3878943 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 GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEIL1	NM_024608.4	c.434+2T>C		splice_donor_variant		ENST00000355059.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEIL1	ENST00000355059.9	c.434+2T>C		splice_donor_variant		2	NM_024608.4	P1

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1055 AN: 152170 Hom.: 6 Cov.: 33

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.: 16 AF XY: 0.00760 AC XY: 981 AN XY: 129088

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.: 31 AF XY: 0.0106 AC XY: 7632 AN XY: 719006

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.: 6 Cov.: 33 AF XY: 0.00624 AC XY: 465 AN XY: 74484

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.: 14

Bravo AF: 0.00725

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00164 AC: 7

ESP6500EA AF: 0.0126 AC: 105

ExAC AF: 0.00681 AC: 821

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 25525159, 18515411, 26662719) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NEIL1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	D;D;D
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

Other links and lift over

dbSNP: rs5745908; hg19: chr15-75641682; COSMIC: COSV61833452; COSMIC: COSV61833452;