16-14552104-G-T

Variant names:

• chr16-14552104-G-T
• rs530099133
• NM_002582.4:c.1406-9C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002582.4(PARN):​c.1406-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PARN NM_002582.4 intron
• Scores: Splicing: ADA: 0.9325
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.92
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARN	NM_002582.4	c.1406-9C>A		intron_variant	Intron 20 of 23	ENST00000437198.7	NP_002573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARN	ENST00000437198.7	c.1406-9C>A		intron_variant	Intron 20 of 23	1	NM_002582.4	ENSP00000387911.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429240 Hom.: 0 Cov.: 24 AF XY: 0.00000140 AC XY: 1 AN XY: 712572

African (AFR) AF: 0.00 AC: 0 AN: 32810

American (AMR) AF: 0.00 AC: 0 AN: 43838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39412

South Asian (SAS) AF: 0.00 AC: 0 AN: 84548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084774

Other (OTH) AF: 0.00 AC: 0 AN: 59168

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	21
DANN	Benign	0.62
PhyloP100		-2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2
DS_AL_spliceai		0.24		Position offset: -9

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

Other links and lift over

dbSNP: rs530099133; hg19: chr16-14645961;