2-55635931-TTCTA-T

Variant names:

• chr2-55635931-TTCTA-T
• rs3838524
• NM_033109.5:c.*302_*305delTAGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_033109.5(PNPT1):​c.*302_*305delTAGA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 167,482 control chromosomes in the GnomAD database, including 8,179 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7247 hom., cov: 0)
  • Exomes 𝑓: 0.34 (932 hom.)
• Consequence: PNPT1 NM_033109.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03
• Publications: 2 publications found

Genes affected

PNPT1 (HGNC:23166): (polyribonucleotide nucleotidyltransferase 1) The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

PNPT1 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia type 25

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 70

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-55635931-TTCTA-T is Benign according to our data. Variant chr2-55635931-TTCTA-T is described in ClinVar as Benign. ClinVar VariationId is 1251542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033109.5. 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
	PNPT1	NM_033109.5	MANE Select	c.*302_*305delTAGA		3_prime_UTR	Exon 28 of 28	NP_149100.2	Q8TCS8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.*302_*305delTAGA		3_prime_UTR	Exon 28 of 28	ENSP00000400646.2	Q8TCS8
	PNPT1	ENST00000917023.1		c.*302_*305delTAGA		3_prime_UTR	Exon 28 of 28	ENSP00000587082.1
	PNPT1	ENST00000949801.1		c.*302_*305delTAGA		3_prime_UTR	Exon 28 of 28	ENSP00000619860.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46593 AN: 151670 Hom.: 7246 Cov.: 0

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.344 AC: 5398 AN: 15696 Hom.: 932 AF XY: 0.341 AC XY: 2909 AN XY: 8542

African (AFR) AF: 0.274 AC: 121 AN: 442

American (AMR) AF: 0.391 AC: 361 AN: 924

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 147 AN: 432

East Asian (EAS) AF: 0.393 AC: 356 AN: 906

South Asian (SAS) AF: 0.411 AC: 341 AN: 830

European-Finnish (FIN) AF: 0.357 AC: 135 AN: 378

Middle Eastern (MID) AF: 0.313 AC: 20 AN: 64

European-Non Finnish (NFE) AF: 0.335 AC: 3640 AN: 10862

Other (OTH) AF: 0.323 AC: 277 AN: 858

GnomAD4 genome AF: 0.307 AC: 46612 AN: 151786 Hom.: 7247 Cov.: 0 AF XY: 0.308 AC XY: 22831 AN XY: 74174

African (AFR) AF: 0.257 AC: 10641 AN: 41390

American (AMR) AF: 0.337 AC: 5135 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1095 AN: 3464

East Asian (EAS) AF: 0.353 AC: 1821 AN: 5154

South Asian (SAS) AF: 0.391 AC: 1881 AN: 4816

European-Finnish (FIN) AF: 0.305 AC: 3213 AN: 10520

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.320 AC: 21741 AN: 67892

Other (OTH) AF: 0.289 AC: 609 AN: 2104

Alfa AF: 0.313 Hom.: 886

Bravo AF: 0.309

Asia WGS AF: 0.336 AC: 1166 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3838524; hg19: chr2-55863066; COSMIC: COSV53176211; COSMIC: COSV53176211;