15-75351274-CTTTTTTTTT-CTTTTTTT

Variant names:

• chr15-75351274-CTT-C
• rs11422837
• NM_024608.4:c.435-819_435-818delTT

Variant summary

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

The NM_001352519.2(NEIL1):​c.100-9_100-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 328,410 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 0.00036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.042 (0 hom.)
• Consequence: NEIL1 NM_001352519.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0676) population. However there is too low homozygotes in high coverage region: (expected more than 58, 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	NM_024608.4	MANE Select	c.435-819_435-818delTT		intron	N/A	NP_078884.2	Q96FI4
	NEIL1	NM_001256552.1		c.693-819_693-818delTT		intron	N/A	NP_001243481.1	Q96FI4
	NEIL1	NM_001352520.2		c.129-819_129-818delTT		intron	N/A	NP_001339449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	ENST00000355059.9	TSL:2 MANE Select	c.435-836_435-835delTT		intron	N/A	ENSP00000347170.4	Q96FI4
	NEIL1	ENST00000569035.5	TSL:1	c.435-836_435-835delTT		intron	N/A	ENSP00000455730.1	Q96FI4
	NEIL1	ENST00000866915.1		c.435-836_435-835delTT		intron	N/A	ENSP00000536974.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 43 AN: 121100 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000692

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000729

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0421 AC: 8732 AN: 207316 Hom.: 0 AF XY: 0.0396 AC XY: 4706 AN XY: 118876

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

African (AFR) AF: 0.0739 AC: 353 AN: 4774

American (AMR) AF: 0.0503 AC: 742 AN: 14748

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 313 AN: 6898

East Asian (EAS) AF: 0.0432 AC: 323 AN: 7482

South Asian (SAS) AF: 0.0348 AC: 1404 AN: 40328

European-Finnish (FIN) AF: 0.0388 AC: 323 AN: 8318

Middle Eastern (MID) AF: 0.0402 AC: 29 AN: 722

European-Non Finnish (NFE) AF: 0.0419 AC: 4797 AN: 114404

Other (OTH) AF: 0.0465 AC: 448 AN: 9642

⚠️ 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.

GnomAD4 genome AF: 0.000355 AC: 43 AN: 121094 Hom.: 0 Cov.: 0 AF XY: 0.000390 AC XY: 22 AN XY: 56358

African (AFR) AF: 0.000691 AC: 23 AN: 33294

American (AMR) AF: 0.000268 AC: 3 AN: 11186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3114

East Asian (EAS) AF: 0.00 AC: 0 AN: 3904

South Asian (SAS) AF: 0.00 AC: 0 AN: 3602

European-Finnish (FIN) AF: 0.000729 AC: 3 AN: 4114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.000236 AC: 14 AN: 59204

Other (OTH) AF: 0.00 AC: 0 AN: 1636

Alfa AF: 0.00 Hom.: 282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11422837; hg19: chr15-75643615;