rs1555740650

Positions:

• chr19-49596253-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020719.3(PRR12):​c.1918G>T​(p.Glu640*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRR12 NM_020719.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.49

Genes affected

PRR12 (HGNC:29217): (proline rich 12) This gene encodes a proline-rich protein that contains two A-T hook DNA binding domains. A chromosomal translocation and gene fusion between this gene and zinc finger, MIZ-type containing 1 (Gene ID: 57178) may underlie intellectual disability and neuropsychiatric problems in a human patient. Enriched expression of this gene in embryonic mouse brain suggests that this gene may play a role in nervous system development. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-49596253-G-T is Pathogenic according to our data. Variant chr19-49596253-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 446254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49596253-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRR12	NM_020719.3	c.1918G>T	p.Glu640*	stop_gained	4/14	ENST00000418929.7	NP_065770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRR12	ENST00000418929.7	c.1918G>T	p.Glu640*	stop_gained	4/14	5	NM_020719.3	ENSP00000394510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroocular syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Mar 18, 2022	This variant is interpreted as pathogenic for Neuroocular syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo with paternity and maternity confirmed (PS2); Predicted nullvariant in a gene where LOF is a known mechanism of disease (PVS1 downgraded to strong). -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -

Neuroocular syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 30, 2024

- -

Autism;C0240063:Iris coloboma;C0454644:Delayed speech and language development;C1854301:Motor delay;C4025846:Abnormality of vision Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 15, 2017

This variant was seen once in our laboratory de novo in a 4.9-year-old female with microcephaly, iris coloboma, brilliant irises, exotropia, delayed motor milestones, delayed speech, suspected autism, congenital hypotonia, abnormal gait, dysmorphic features, failure to thrive and a history of prematurity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.21
GERP RS		3.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555740650; hg19: chr19-50099510;