NM_002582.4:c.1895T>C

Variant names:

• chr16-14436742-A-G
• rs1960718749
• NM_002582.4:c.1895T>C

Variant summary

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

The NM_002582.4(PARN):​c.1895T>C​(p.Leu632Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,020 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L632R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PARN NM_002582.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARN	NM_002582.4	MANE Select	c.1895T>C	p.Leu632Pro	missense	Exon 24 of 24	NP_002573.1	O95453-1
	PARN	NM_001242992.2		c.1757T>C	p.Leu586Pro	missense	Exon 23 of 23	NP_001229921.1	O95453-3
	PARN	NM_001134477.3		c.1712T>C	p.Leu571Pro	missense	Exon 24 of 24	NP_001127949.1	O95453-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARN	ENST00000437198.7	TSL:1 MANE Select	c.1895T>C	p.Leu632Pro	missense	Exon 24 of 24	ENSP00000387911.2	O95453-1
	PARN	ENST00000931608.1		c.2051T>C	p.Leu684Pro	missense	Exon 24 of 24	ENSP00000601667.1
	PARN	ENST00000650990.1		c.1970T>C	p.Leu657Pro	missense	Exon 25 of 25	ENSP00000498741.1	A0A494C0W0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449020 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 719220

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 42708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.00 AC: 0 AN: 83372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106024

Other (OTH) AF: 0.00 AC: 0 AN: 59984

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.77
MutPred		0.32		Loss of sheet (P = 0.0037)
MVP		0.56
MPC		0.76
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.50

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: rs1960718749; hg19: chr16-14530599;