Genetic Variant NEIL1:c.435-820_435-818delTTT (chr15-75351274-CTTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001352519.2(NEIL1):c.100-10_100-8delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 347,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0081 ( 0 hom. )

Consequence

NEIL1
NM_001352519.2 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.212

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the AFR (0.0167) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352519.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEIL1	NM_024608.4	MANE Select	c.435-820_435-818delTTT	intron	N/A	NP_078884.2	Q96FI4
NEIL1	NM_001256552.1		c.693-820_693-818delTTT	intron	N/A	NP_001243481.1	Q96FI4
NEIL1	NM_001352520.2		c.129-820_129-818delTTT	intron	N/A	NP_001339449.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEIL1	ENST00000355059.9	TSL:2 MANE Select	c.435-836_435-834delTTT	intron	N/A	ENSP00000347170.4	Q96FI4
NEIL1	ENST00000569035.5	TSL:1	c.435-836_435-834delTTT	intron	N/A	ENSP00000455730.1	Q96FI4
NEIL1	ENST00000866915.1		c.435-836_435-834delTTT	intron	N/A	ENSP00000536974.1

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

121124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000553

Gnomad FIN

AF:

0.000243

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000355

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00813

AC:

1843

AN:

226628

Hom.:

AF XY:

0.00755

AC XY:

984

AN XY:

130412

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0198

AC:

104

AN:

5250

American (AMR)

AF:

0.0119

AC:

186

AN:

15668

Ashkenazi Jewish (ASJ)

AF:

0.00926

AC:

AN:

7340

East Asian (EAS)

AF:

0.0130

AC:

102

AN:

7848

South Asian (SAS)

AF:

0.00546

AC:

240

AN:

43948

European-Finnish (FIN)

AF:

0.00707

AC:

AN:

9052

Middle Eastern (MID)

AF:

0.00633

AC:

AN:

790

European-Non Finnish (NFE)

AF:

0.00786

AC:

992

AN:

126182

Other (OTH)

AF:

0.00777

AC:

AN:

10550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

268

536

803

1071

1339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000198

AC:

AN:

121124

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

AN XY:

56364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.00

AC:

AN:

11186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3114

East Asian (EAS)

AF:

0.00

AC:

AN:

3918

South Asian (SAS)

AF:

0.000553

AC:

AN:

3614

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

4122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.000355

AC:

AN:

59232

Other (OTH)

AF:

0.00

AC:

AN:

1622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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15-75351274-CTTTTTTTTT-CTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over