chr15-34341926-A-AG

Variant names:

• chr15-34341926-A-AG
• rs528879821
• NM_018648.4:c.*41dupC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_018648.4(NOP10):​c.*41dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,609,704 control chromosomes in the GnomAD database, including 64 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (59 hom.)
• Consequence: NOP10 NM_018648.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0120
• Publications: 0 publications found

Genes affected

NOP10 (HGNC:14378): (NOP10 ribonucleoprotein) This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA processing and modification and have been classified into two families: C/D and H/ACA. The H/ACA snoRNPs also include the DKC1, NOLA1 and NOLA2 proteins. These four H/ACA snoRNP proteins localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. The four H/ACA snoRNP proteins are also components of the telomerase complex. This gene encodes a protein related to Saccharomyces cerevisiae Nop10p. [provided by RefSeq, Jul 2008]

NOP10 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 1

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 15-34341926-A-AG is Benign according to our data. Variant chr15-34341926-A-AG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 315634.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018648.4. 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
	NOP10	NM_018648.4	MANE Select	c.*41dupC		3_prime_UTR	Exon 2 of 2	NP_061118.1	Q9NPE3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOP10	ENST00000328848.6	TSL:1 MANE Select	c.*41dupC		3_prime_UTR	Exon 2 of 2	ENSP00000332198.5	Q9NPE3
	NOP10	ENST00000699935.1		c.*41dupC		3_prime_UTR	Exon 2 of 2	ENSP00000514698.1	A0A8V8TQE9
	NOP10	ENST00000699926.1		c.*41dupC		3_prime_UTR	Exon 2 of 2	ENSP00000514692.1	A0A8V8TQE5

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152140 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00542 AC: 1356 AN: 250332 AF XY: 0.00537

Gnomad AFR exome AF: 0.00186

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00874

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00765 AC: 11148 AN: 1457446 Hom.: 59 Cov.: 30 AF XY: 0.00747 AC XY: 5419 AN XY: 725240

African (AFR) AF: 0.00111 AC: 37 AN: 33370

American (AMR) AF: 0.00123 AC: 55 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00121 AC: 104 AN: 86074

European-Finnish (FIN) AF: 0.00952 AC: 508 AN: 53364

Middle Eastern (MID) AF: 0.000677 AC: 3 AN: 4430

European-Non Finnish (NFE) AF: 0.00903 AC: 10021 AN: 1109596

Other (OTH) AF: 0.00666 AC: 401 AN: 60178

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152258 Hom.: 5 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74438

African (AFR) AF: 0.00166 AC: 69 AN: 41544

American (AMR) AF: 0.00124 AC: 19 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00830 AC: 88 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00867 AC: 590 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00666 Hom.: 2

Bravo AF: 0.00467

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Dyskeratosis Congenita, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.012
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs528879821; hg19: chr15-34634127;