rs73810366

Variant names:

• chr4-41748377-G-A
• rs73810366
• NM_003924.4:c.234C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-41748377-G-A
• chr4-41748377-G-C
• chr4-41748377-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003924.4(PHOX2B):​c.234C>T​(p.Tyr78Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.000608 in 1,614,146 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: PHOX2B NM_003924.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.87
• Publications: 4 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-AS1 (HGNC:40457): (PHOX2B antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-41748377-G-A is Benign according to our data. Variant chr4-41748377-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00339 (517/152328) while in subpopulation AFR AF = 0.0118 (490/41578). AF 95% confidence interval is 0.0109. There are 4 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 517 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.234C>T	p.Tyr78Tyr	synonymous	Exon 1 of 3	NP_003915.2
	PHOX2B-AS1	NR_187403.1		n.29G>A		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.234C>T	p.Tyr78Tyr	synonymous	Exon 1 of 3	ENSP00000226382.2	Q99453
	PHOX2B-AS1	ENST00000508038.2	TSL:5	n.85G>A		non_coding_transcript_exon	Exon 1 of 5
	PHOX2B-AS1	ENST00000819353.1		n.32G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 515 AN: 152210 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000852 AC: 213 AN: 249900 AF XY: 0.000665

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000318 AC: 465 AN: 1461818 Hom.: 1 Cov.: 31 AF XY: 0.000270 AC XY: 196 AN XY: 727216

African (AFR) AF: 0.0112 AC: 376 AN: 33474

American (AMR) AF: 0.000872 AC: 39 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111978

Other (OTH) AF: 0.000596 AC: 36 AN: 60394

GnomAD4 genome AF: 0.00339 AC: 517 AN: 152328 Hom.: 4 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74480

African (AFR) AF: 0.0118 AC: 490 AN: 41578

American (AMR) AF: 0.00131 AC: 20 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00395

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Neuroblastoma, susceptibility to, 2 (2)
-	-	1	Congenital central hypoventilation (1)
-	-	1	Haddad syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.93
PhyloP100		4.9
PromoterAI		-0.023	Neutral
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73810366; hg19: chr4-41750394; COSMIC: COSV56928303; COSMIC: COSV56928303;