11-72244023-C-G

Variant names:

• chr11-72244023-C-G
• rs140850664
• NM_005169.4:c.-19G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005169.4(PHOX2A):​c.-19G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.000035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00064 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHOX2A NM_005169.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 1 publications found

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]

PHOX2A Gene-Disease associations (from GenCC):

• fibrosis of extraocular muscles, congenital, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.-19G>C		5_prime_UTR_variant	Exon 1 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.-19G>C		5_prime_UTR_variant	Exon 1 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.-19G>C		5_prime_UTR_variant	Exon 1 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.-19G>C		5_prime_UTR_variant	Exon 1 of 3		NP_001412027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2A	ENST00000298231.5	c.-19G>C		5_prime_UTR_variant	Exon 1 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000544057.1	n.85+1557G>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112762 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000835

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000385

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000643 AC: 171 AN: 265900 Hom.: 0 Cov.: 6 AF XY: 0.000668 AC XY: 85 AN XY: 127282

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

African (AFR) AF: 0.000176 AC: 1 AN: 5686

American (AMR) AF: 0.000309 AC: 1 AN: 3236

Ashkenazi Jewish (ASJ) AF: 0.000739 AC: 2 AN: 2706

East Asian (EAS) AF: 0.00101 AC: 7 AN: 6946

South Asian (SAS) AF: 0.000480 AC: 3 AN: 6250

European-Finnish (FIN) AF: 0.00263 AC: 35 AN: 13330

Middle Eastern (MID) AF: 0.00427 AC: 3 AN: 702

European-Non Finnish (NFE) AF: 0.000539 AC: 117 AN: 217220

Other (OTH) AF: 0.000204 AC: 2 AN: 9824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000355 AC: 4 AN: 112762 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 1 AN XY: 55604

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

African (AFR) AF: 0.0000325 AC: 1 AN: 30732

American (AMR) AF: 0.0000835 AC: 1 AN: 11972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2776

East Asian (EAS) AF: 0.00 AC: 0 AN: 3592

South Asian (SAS) AF: 0.00 AC: 0 AN: 3134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000385 AC: 2 AN: 51886

Other (OTH) AF: 0.00 AC: 0 AN: 1534

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.76
PhyloP100		2.6
PromoterAI		0.038	Neutral
Mutation Taster		=295/5	polymorphism

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: rs140850664; hg19: chr11-71955067;