rs779913205

Variant names:

• chr4-41746072-G-A
• rs779913205
• NM_003924.4:c.680C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-41746072-G-A
• chr4-41746072-G-C
• chr4-41746072-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003924.4(PHOX2B):​c.680C>T​(p.Ala227Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,280,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A227E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PHOX2B NM_003924.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.365
• Publications: 1 publications found

Genes affected

PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

PHOX2B Gene-Disease associations (from GenCC):

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• neuroblastoma, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• congenital central hypoventilation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10814962).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003924.4. 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
	PHOX2B	NM_003924.4	MANE Select	c.680C>T	p.Ala227Val	missense	Exon 3 of 3	NP_003915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.680C>T	p.Ala227Val	missense	Exon 3 of 3	ENSP00000226382.2
	PHOX2B	ENST00000510424.2	TSL:3	n.501C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000203 AC: 2 AN: 98750 AF XY: 0.0000175

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: 0.0000205

Gnomad OTH exome AF: 0.000421

GnomAD4 exome AF: 0.00000625 AC: 8 AN: 1280558 Hom.: 0 Cov.: 31 AF XY: 0.00000475 AC XY: 3 AN XY: 631446

African (AFR) AF: 0.00 AC: 0 AN: 26274

American (AMR) AF: 0.00 AC: 0 AN: 22042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20500

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 60868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32598

Middle Eastern (MID) AF: 0.000551 AC: 2 AN: 3630

European-Non Finnish (NFE) AF: 9.69e-7 AC: 1 AN: 1032318

Other (OTH) AF: 0.0000959 AC: 5 AN: 52140

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000471 Hom.: 0

ExAC AF: 0.00000899 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.36
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.14
Sift	Benign	0.46	T
Sift4G	Benign	0.64	T
Polyphen		0.22	B
Vest4		0.22
MutPred		0.30		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.93
MPC		1.1
ClinPred		0.024	T
GERP RS		1.5
Varity_R		0.055
gMVP		0.48
Mutation Taster		=90/10	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: rs779913205; hg19: chr4-41748089; COSMIC: COSV99891728; COSMIC: COSV99891728;