dbSNP rs59687658: PARN:c.840+6T>C (chr16-14599898-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_002582.4(PARN):c.840+6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00144 in 1,586,058 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 24 hom. )

Consequence

PARN
NM_002582.4 splice_region, intron

Scores

Splicing: ADA: 0.5625

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 5.42

Publications

6 publications found

Variant links:

Genes affected

PARN (HGNC:8609): (poly(A)-specific ribonuclease) The protein encoded by this gene is a 3'-exoribonuclease, with similarity to the RNase D family of 3'-exonucleases. It prefers poly(A) as the substrate, hence, efficiently degrades poly(A) tails of mRNAs. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. This protein is also involved in silencing of certain maternal mRNAs during oocyte maturation and early embryonic development, as well as in nonsense-mediated decay (NMD) of mRNAs that contain premature stop codons. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

PARN Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal recessive 6
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PARN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002582.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 16-14599898-A-G is Benign according to our data. Variant chr16-14599898-A-G is described in ClinVar as Benign. ClinVar VariationId is 436151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0023 (347/151048) while in subpopulation EAS AF = 0.016 (83/5186). AF 95% confidence interval is 0.0132. There are 4 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002582.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PARN	NM_002582.4	MANE Select	c.840+6T>C	splice_region intron	N/A	NP_002573.1	O95453-1
PARN	NM_001242992.2		c.702+6T>C	splice_region intron	N/A	NP_001229921.1	O95453-3
PARN	NM_001134477.3		c.657+6T>C	splice_region intron	N/A	NP_001127949.1	O95453-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PARN	ENST00000437198.7	TSL:1 MANE Select	c.840+6T>C	splice_region intron	N/A	ENSP00000387911.2	O95453-1
PARN	ENST00000931608.1		c.840+6T>C	splice_region intron	N/A	ENSP00000601667.1
PARN	ENST00000650990.1		c.840+6T>C	splice_region intron	N/A	ENSP00000498741.1	A0A494C0W0

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

348

AN:

150936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00238

AC:

577

AN:

242122

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.00443

Gnomad ASJ exome

AF:

0.000608

Gnomad EAS exome

AF:

0.0138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000386

Gnomad OTH exome

AF:

0.00238

GnomAD4 exome

AF:

0.00135

AC:

1932

AN:

1435010

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

1003

AN XY:

714954

show subpopulations

African (AFR)

AF:

0.000250

AC:

AN:

31956

American (AMR)

AF:

0.00388

AC:

166

AN:

42810

Ashkenazi Jewish (ASJ)

AF:

0.000620

AC:

AN:

25814

East Asian (EAS)

AF:

0.0225

AC:

885

AN:

39322

South Asian (SAS)

AF:

0.00417

AC:

348

AN:

83466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00474

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000347

AC:

380

AN:

1093544

Other (OTH)

AF:

0.00172

AC:

102

AN:

59318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

174

261

348

435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00230

AC:

347

AN:

151048

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

221

AN XY:

73866

show subpopulations

African (AFR)

AF:

0.000396

AC:

AN:

40362

American (AMR)

AF:

0.0119

AC:

182

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0160

AC:

AN:

5186

South Asian (SAS)

AF:

0.00643

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68034

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000197

Hom.:

Bravo

AF:

0.00198

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4;C4225356:Dyskeratosis congenita, autosomal recessive 6 (1)

Pulmonary fibrosis;na:Familial Interstitial Pneumonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.56

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: -42

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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