Variant 4-41745990-TGCCGCCGCCGCCGCTGCCGCGGCCGCC-TGCCGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003924.4(PHOX2B):c.741_761del(p.Ala254_Ala260del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,235,952 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 8 hom. )

Consequence

PHOX2B
NM_003924.4 inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.12

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003924.4

BP6

Variant 4-41745990-TGCCGCCGCCGCCGCTGCCGCG-T is Benign according to our data. Variant chr4-41745990-TGCCGCCGCCGCCGCTGCCGCG-T is described in ClinVar as [Likely_benign]. Clinvar id is 239591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745990-TGCCGCCGCCGCCGCTGCCGCG-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000457 (67/146766) while in subpopulation AMR AF= 0.000894 (13/14544). AF 95% confidence interval is 0.000529. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.741_761del	p.Ala254_Ala260del	inframe_deletion	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.741_761del	p.Ala254_Ala260del	inframe_deletion	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000450

AC:

AN:

146666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000713

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000895

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:

0.000348

Gnomad OTH

AF:

0.000496

GnomAD3 exomes

AF:

0.000279

AC:

AN:

21500

Hom.:

AF XY:

0.000151

AC XY:

AN XY:

13204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00262

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:

0.000325

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000340

AC:

370

AN:

1089186

Hom.:

AF XY:

0.000325

AC XY:

170

AN XY:

522640

show subpopulations

Gnomad4 AFR exome

AF:

0.000454

Gnomad4 AMR exome

AF:

0.000836

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000416

Gnomad4 SAS exome

AF:

0.000642

Gnomad4 FIN exome

AF:

0.000109

Gnomad4 NFE exome

AF:

0.000346

Gnomad4 OTH exome

AF:

0.000305

GnomAD4 genome

AF:

0.000457

AC:

AN:

146766

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

AN XY:

71486

show subpopulations

Gnomad4 AFR

AF:

0.000736

Gnomad4 AMR

AF:

0.000894

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000348

Gnomad4 OTH

AF:

0.000490

Bravo

AF:

0.000385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PHOX2B: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 27535533) -

Haddad syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over