rs200677089

Variant names:

• chr16-14436746-T-A
• rs200677089
• NM_002582.4:c.1891A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-14436746-T-A
• chr16-14436746-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_002582.4(PARN):​c.1891A>T​(p.Thr631Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. T631A) 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: 0.434
• 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: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 0 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity PARN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06349179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARN	NM_002582.4	c.1891A>T	p.Thr631Ser	missense_variant	Exon 24 of 24	ENST00000437198.7	NP_002573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARN	ENST00000437198.7	c.1891A>T	p.Thr631Ser	missense_variant	Exon 24 of 24	1	NM_002582.4	ENSP00000387911.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446456 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 717718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.0000237 AC: 1 AN: 42116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.00 AC: 0 AN: 83118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104788

Other (OTH) AF: 0.00 AC: 0 AN: 59914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.020	T;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.
PhyloP100		0.43
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.72	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.14
MutPred		0.13		Gain of glycosylation at T631 (P = 0.0443);.;.;.;
MVP		0.34
MPC		0.12
ClinPred		0.059	T
GERP RS		2.2
Varity_R		0.027
gMVP		0.080

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: rs200677089; hg19: chr16-14530603;