chr15-75349215-G-GC

Variant names:

• chr15-75349215-G-GC
• rs556576971
• NM_024608.4:c.314dupC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6 BS2_Supporting

The NM_024608.4(NEIL1):​c.314dupC​(p.Pro106AlafsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,609,216 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: NEIL1 NM_024608.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.976
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 15-75349215-G-GC is Benign according to our data. Variant chr15-75349215-G-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 595640.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	NM_024608.4	MANE Select	c.314dupC	p.Pro106AlafsTer50	frameshift	Exon 2 of 10	NP_078884.2	Q96FI4
	NEIL1	NM_001256552.1		c.572dupC	p.Pro192AlafsTer50	frameshift	Exon 2 of 10	NP_001243481.1	Q96FI4
	NEIL1	NM_001352519.2		c.-22dupC		5_prime_UTR	Exon 2 of 6	NP_001339448.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	ENST00000355059.9	TSL:2 MANE Select	c.314dupC	p.Pro106AlafsTer50	frameshift	Exon 2 of 10	ENSP00000347170.4	Q96FI4
	NEIL1	ENST00000569035.5	TSL:1	c.314dupC	p.Pro106AlafsTer50	frameshift	Exon 2 of 10	ENSP00000455730.1	Q96FI4
	NEIL1	ENST00000866915.1		c.314dupC	p.Pro106AlafsTer50	frameshift	Exon 2 of 9	ENSP00000536974.1

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00126 AC: 307 AN: 243876 AF XY: 0.00125

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00672

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.00104 AC: 1508 AN: 1456852 Hom.: 2 Cov.: 31 AF XY: 0.00103 AC XY: 745 AN XY: 724976

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00793 AC: 207 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.00425 AC: 208 AN: 48910

Middle Eastern (MID) AF: 0.000535 AC: 3 AN: 5608

European-Non Finnish (NFE) AF: 0.000906 AC: 1007 AN: 1111814

Other (OTH) AF: 0.00118 AC: 71 AN: 60322

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74512

African (AFR) AF: 0.000264 AC: 11 AN: 41598

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00470 AC: 50 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000616

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98
Mutation Taster		=170/30	disease causing (fs/PTC)

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: rs556576971; hg19: chr15-75641556;