16-2046383-G-A

Variant names:

• chr16-2046383-G-A
• rs2233518
• NM_002528.7:c.116-17C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002528.7(NTHL1):​c.116-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,598,958 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0098 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: NTHL1 NM_002528.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.802
• Publications: 1 publications found

Genes affected

NTHL1 (HGNC:8028): (nth like DNA glycosylase 1) The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

NTHL1 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• NTHL1-deficiency tumor predisposition syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• meningioma

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-2046383-G-A is Benign according to our data. Variant chr16-2046383-G-A is described in ClinVar as Benign. ClinVar VariationId is 1284832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0098 (1493/152300) while in subpopulation AFR AF = 0.0341 (1417/41544). AF 95% confidence interval is 0.0326. There are 21 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002528.7. 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
	NTHL1	NM_002528.7	MANE Select	c.116-17C>T		intron	N/A	NP_002519.2
	NTHL1	NM_001318193.2		c.116-17C>T		intron	N/A	NP_001305122.2
	NTHL1	NM_001318194.2		c.-63-17C>T		intron	N/A	NP_001305123.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTHL1	ENST00000651570.2	MANE Select	c.116-17C>T		intron	N/A	ENSP00000498421.1
	NTHL1	ENST00000219066.5	TSL:1	c.140-17C>T		intron	N/A	ENSP00000219066.1
	NTHL1	ENST00000925707.1		c.116-17C>T		intron	N/A	ENSP00000595766.1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1488 AN: 152182 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00267 AC: 656 AN: 245272 AF XY: 0.00193

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00105 AC: 1516 AN: 1446658 Hom.: 19 Cov.: 31 AF XY: 0.000906 AC XY: 650 AN XY: 717606

African (AFR) AF: 0.0347 AC: 1153 AN: 33232

American (AMR) AF: 0.00173 AC: 77 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49384

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5706

European-Non Finnish (NFE) AF: 0.000131 AC: 144 AN: 1102718

Other (OTH) AF: 0.00202 AC: 121 AN: 59828

GnomAD4 genome AF: 0.00980 AC: 1493 AN: 152300 Hom.: 21 Cov.: 32 AF XY: 0.00969 AC XY: 722 AN XY: 74476

African (AFR) AF: 0.0341 AC: 1417 AN: 41544

American (AMR) AF: 0.00327 AC: 50 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00515 Hom.: 4

Bravo AF: 0.0111

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Familial adenomatous polyposis 3 (1)
-	-	1	NTHL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.81
PhyloP100		-0.80
BranchPoint Hunter		2.0
PromoterAI		0.0024	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2233518; hg19: chr16-2096384;