rs5745908

Variant names:

• chr15-75349341-T-C
• rs5745908
• NM_024608.4:c.434+2T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PVS1_Strong BP6_Very_Strong BS2

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
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -8 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.
• BP6: Variant 15-75349341-T-C is Benign according to our data. Variant chr15-75349341-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 790285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024608.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	NM_024608.4	MANE Select	c.434+2T>C		splice_donor intron	N/A	NP_078884.2
	NEIL1	NM_001256552.1		c.692+2T>C		splice_donor intron	N/A	NP_001243481.1
	NEIL1	NM_001352520.2		c.128+2T>C		splice_donor intron	N/A	NP_001339449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	ENST00000355059.9	TSL:2 MANE Select	c.434+2T>C		splice_donor intron	N/A	ENSP00000347170.4
	NEIL1	ENST00000569035.5	TSL:1	c.434+2T>C		splice_donor intron	N/A	ENSP00000455730.1
	NEIL1	ENST00000564951.1	TSL:2	n.590T>C		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes AF: 0.00716 AC: 1689 AN: 235788 AF XY: 0.00760

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 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

African (AFR) AF: 0.00148 AC: 49 AN: 33216

American (AMR) AF: 0.00558 AC: 246 AN: 44068

Ashkenazi Jewish (ASJ) AF: 0.00275 AC: 70 AN: 25414

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39488

South Asian (SAS) AF: 0.00136 AC: 116 AN: 85154

European-Finnish (FIN) AF: 0.00220 AC: 111 AN: 50404

Middle Eastern (MID) AF: 0.00683 AC: 39 AN: 5710

European-Non Finnish (NFE) AF: 0.0130 AC: 14320 AN: 1104832

Other (OTH) AF: 0.00956 AC: 572 AN: 59810

GnomAD4 genome AF: 0.00693 AC: 1055 AN: 152288 Hom.: 6 Cov.: 33 AF XY: 0.00624 AC XY: 465 AN XY: 74484

African (AFR) AF: 0.00197 AC: 82 AN: 41558

American (AMR) AF: 0.00516 AC: 79 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 835 AN: 68010

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0108 Hom.: 27

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.3
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

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