21-32743263-A-C

Variant names:

• chr21-32743263-A-C
• rs1466452056
• NM_016631.4:c.2319T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016631.4(PAXBP1):​c.2319T>G​(p.Phe773Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAXBP1 NM_016631.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

Genes affected

PAXBP1 (HGNC:13579): (PAX3 and PAX7 binding protein 1) Predicted to enable DNA binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to act upstream of or within positive regulation of histone methylation; positive regulation of myoblast proliferation; and regulation of skeletal muscle satellite cell proliferation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PAXBP1-AS1 (HGNC:39603): (PAXBP1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAXBP1	NM_016631.4	c.2319T>G	p.Phe773Leu	missense_variant	Exon 15 of 18	ENST00000331923.9	NP_057715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAXBP1	ENST00000331923.9	c.2319T>G	p.Phe773Leu	missense_variant	Exon 15 of 18	1	NM_016631.4	ENSP00000328992.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000463 AC: 1 AN: 216132 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 117482

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: 0.00000961

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2319T>G (p.F773L) alteration is located in exon 15 (coding exon 15) of the PAXBP1 gene. This alteration results from a T to G substitution at nucleotide position 2319, causing the phenylalanine (F) at amino acid position 773 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.22	T;D
Polyphen		0.78	P;D
Vest4		0.64
MutPred		0.58		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.45
MPC		1.1
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs1466452056; hg19: chr21-34115574;