4-41746494-T-G

Position:

• chr4-41746494-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003924.4(PHOX2B):​c.430-172A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,944 control chromosomes in the GnomAD database, including 12,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.37 (12099 hom., cov: 32)
• Consequence: PHOX2B NM_003924.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.12

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-41746494-T-G is Benign according to our data. Variant chr4-41746494-T-G is described in ClinVar as [Benign]. Clinvar id is 1247551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.430-172A>C		intron_variant		ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.430-172A>C		intron_variant		1	NM_003924.4	P1
PHOX2B	ENST00000510424.2	n.251-172A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56272 AN: 151826 Hom.: 12082 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.319

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.371 AC: 56327 AN: 151944 Hom.: 12099 Cov.: 32 AF XY: 0.365 AC XY: 27135 AN XY: 74270

Gnomad4 AFR AF: 0.600

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.342

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.287

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.317

Alfa AF: 0.174 Hom.: 348

Bravo AF: 0.375

Asia WGS AF: 0.298 AC: 1036 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs2196822; hg19: chr4-41748511;