11-72243787-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_005169.4(PHOX2A):​c.217+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000183 in 1,094,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

PHOX2A
NM_005169.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.13
Variant links:
Genes affected
PHOX2A (HGNC:691): (paired like homeobox 2A) The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. The encoded protein plays a central role in development of the autonomic nervous system. It regulates the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, two catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype. The encoded protein has also been shown to regulate transcription of the alpha3 nicotinic acetylcholine receptor gene. Mutations in this gene have been associated with autosomal recessive congenital fibrosis of the extraocular muscles. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-72243787-C-T is Pathogenic according to our data. Variant chr11-72243787-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6838.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PHOX2ANM_005169.4 linkc.217+1G>A splice_donor_variant, intron_variant Intron 1 of 2 ENST00000298231.5 NP_005160.2 O14813
PHOX2ANM_001425096.1 linkc.217+1G>A splice_donor_variant, intron_variant Intron 1 of 2 NP_001412025.1
PHOX2ANM_001425097.1 linkc.217+1G>A splice_donor_variant, intron_variant Intron 1 of 2 NP_001412026.1
PHOX2ANM_001425098.1 linkc.217+1G>A splice_donor_variant, intron_variant Intron 1 of 2 NP_001412027.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PHOX2AENST00000298231.5 linkc.217+1G>A splice_donor_variant, intron_variant Intron 1 of 2 1 NM_005169.4 ENSP00000298231.5 O14813
PHOX2AENST00000544057.1 linkn.85+1793G>A intron_variant Intron 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000183
AC:
2
AN:
1094506
Hom.:
0
Cov.:
31
AF XY:
0.00000385
AC XY:
2
AN XY:
519574
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000216
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Fibrosis of extraocular muscles, congenital, 2 Pathogenic:1
Nov 01, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
4.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1590729541; hg19: chr11-71954831; API