11-72244023-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005169.4(PHOX2A):​c.-19G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 378,646 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (40 hom., cov: 30)
  • Exomes 𝑓: 0.025 (79 hom.)
• Consequence: PHOX2A NM_005169.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-72244023-C-T is Benign according to our data. Variant chr11-72244023-C-T is described in ClinVar as Benign. ClinVar VariationId is 259654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.-19G>A		5_prime_UTR_variant	Exon 1 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.-19G>A		5_prime_UTR_variant	Exon 1 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.-19G>A		5_prime_UTR_variant	Exon 1 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.-19G>A		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>A		5_prime_UTR_variant	Exon 1 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000544057.1	n.85+1557G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2218 AN: 112726 Hom.: 40 Cov.: 30

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00868

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.00413

Gnomad MID AF: 0.0231

Gnomad NFE AF: 0.00825

Gnomad OTH AF: 0.0169

GnomAD2 exomes AF: 0.0144 AC: 328 AN: 22810 AF XY: 0.0152

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.0522

Gnomad ASJ exome AF: 0.00990

Gnomad EAS exome AF: 0.0726

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0248 AC: 6586 AN: 265884 Hom.: 79 Cov.: 6 AF XY: 0.0252 AC XY: 3205 AN XY: 127272

African (AFR) AF: 0.0478 AC: 272 AN: 5686

American (AMR) AF: 0.118 AC: 380 AN: 3230

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 203 AN: 2702

East Asian (EAS) AF: 0.193 AC: 1336 AN: 6914

South Asian (SAS) AF: 0.0846 AC: 528 AN: 6240

European-Finnish (FIN) AF: 0.00763 AC: 102 AN: 13360

Middle Eastern (MID) AF: 0.0743 AC: 52 AN: 700

European-Non Finnish (NFE) AF: 0.0150 AC: 3261 AN: 217244

Other (OTH) AF: 0.0461 AC: 452 AN: 9808

GnomAD4 genome AF: 0.0197 AC: 2217 AN: 112762 Hom.: 40 Cov.: 30 AF XY: 0.0213 AC XY: 1185 AN XY: 55600

African (AFR) AF: 0.0197 AC: 607 AN: 30750

American (AMR) AF: 0.0397 AC: 476 AN: 11988

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 72 AN: 2774

East Asian (EAS) AF: 0.105 AC: 377 AN: 3580

South Asian (SAS) AF: 0.0622 AC: 195 AN: 3134

European-Finnish (FIN) AF: 0.00413 AC: 26 AN: 6300

Middle Eastern (MID) AF: 0.0252 AC: 6 AN: 238

European-Non Finnish (NFE) AF: 0.00825 AC: 428 AN: 51880

Other (OTH) AF: 0.0162 AC: 25 AN: 1542

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.0174

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		2.6
PromoterAI		-0.014	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;