rs749694204

chr4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-Tchr4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-TGCCchr4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-TGCCGCC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_003924.4(PHOX2B):c.735_761del(p.Ala252_Ala260del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,235,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A245A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PHOX2B NM_003924.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.12

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-T is Benign according to our data. Variant chr4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 467740.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.735_761del	p.Ala252_Ala260del	inframe_deletion	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.735_761del	p.Ala252_Ala260del	inframe_deletion	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000477 AC: 7 AN: 146666 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000689

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00149

GnomAD3 exomes AF: 0.0000465 AC: 1 AN: 21500 Hom.: 0 AF XY: 0.0000757 AC XY: 1 AN XY: 13204

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000257 AC: 28 AN: 1089222 Hom.: 0 AF XY: 0.0000249 AC XY: 13 AN XY: 522656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000478

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000428

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000195

Gnomad4 OTH exome AF: 0.0000704

GnomAD4 genome AF: 0.0000477 AC: 7 AN: 146666 Hom.: 0 Cov.: 32 AF XY: 0.0000841 AC XY: 6 AN XY: 71376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000689

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000422

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000151

Gnomad4 OTH AF: 0.00149

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Haddad syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749694204; hg19: chr4-41748007;