chr11-72243803-C-G

Variant names:

• chr11-72243803-C-G
• rs764865688
• NM_005169.4:c.202G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005169.4(PHOX2A):​c.202G>C​(p.Ala68Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,249,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A68T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PHOX2A NM_005169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.359
• Publications: 0 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), G2P, Genomics England PanelApp
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22224352).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005169.4. 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
	PHOX2A	NM_005169.4	MANE Select	c.202G>C	p.Ala68Pro	missense	Exon 1 of 3	NP_005160.2
	PHOX2A	NM_001425096.1		c.202G>C	p.Ala68Pro	missense	Exon 1 of 3	NP_001412025.1
	PHOX2A	NM_001425097.1		c.202G>C	p.Ala68Pro	missense	Exon 1 of 3	NP_001412026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	ENST00000298231.5	TSL:1 MANE Select	c.202G>C	p.Ala68Pro	missense	Exon 1 of 3	ENSP00000298231.5	O14813
	PHOX2A	ENST00000544057.1	TSL:3	n.85+1777G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000191

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000251 AC: 1 AN: 3982 AF XY: 0.000526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000451

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 130 AN: 1096964 Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 55 AN XY: 520856

African (AFR) AF: 0.00 AC: 0 AN: 23040

American (AMR) AF: 0.00 AC: 0 AN: 8492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14582

East Asian (EAS) AF: 0.00 AC: 0 AN: 26582

South Asian (SAS) AF: 0.00 AC: 0 AN: 25542

European-Finnish (FIN) AF: 0.0000420 AC: 1 AN: 23834

Middle Eastern (MID) AF: 0.000338 AC: 1 AN: 2960

European-Non Finnish (NFE) AF: 0.000135 AC: 125 AN: 927740

Other (OTH) AF: 0.0000679 AC: 3 AN: 44192

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67988

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000176 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.36
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.041	D
Polyphen		0.43	B
Vest4		0.24
MVP		0.64
ClinPred		0.16	T
GERP RS		4.3
PromoterAI		-0.045	Neutral
Varity_R		0.37
gMVP		0.65
Mutation Taster		=77/23	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: rs764865688; hg19: chr11-71954847;