NM_004571.5:c.1076C>A

Variant names:

• chr21-43028851-C-A
• rs757892846
• NM_004571.5:c.1076C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004571.5(PKNOX1):​c.1076C>A​(p.Pro359Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P359L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKNOX1 NM_004571.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• Publications: 0 publications found

Genes affected

PKNOX1 (HGNC:9022): (PBX/knotted 1 homeobox 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in angiogenesis and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within camera-type eye development; hemopoiesis; and positive regulation of transcription by RNA polymerase II. Predicted to be located in cytoplasm and nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17060947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004571.5. 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
	PKNOX1	NM_004571.5	MANE Select	c.1076C>A	p.Pro359Gln	missense	Exon 10 of 11	NP_004562.2
	PKNOX1	NM_001320694.2		c.1073C>A	p.Pro358Gln	missense	Exon 10 of 11	NP_001307623.1
	PKNOX1	NM_001286258.2		c.725C>A	p.Pro242Gln	missense	Exon 9 of 10	NP_001273187.1	E7EPN6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKNOX1	ENST00000291547.10	TSL:1 MANE Select	c.1076C>A	p.Pro359Gln	missense	Exon 10 of 11	ENSP00000291547.4	P55347-1
	PKNOX1	ENST00000911566.1		c.1199C>A	p.Pro400Gln	missense	Exon 11 of 12	ENSP00000581625.1
	PKNOX1	ENST00000883907.1		c.1196C>A	p.Pro399Gln	missense	Exon 11 of 12	ENSP00000553966.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.23
Sift	Uncertain	0.012	D
Sift4G	Benign	0.59	T
Polyphen		0.010	B
Vest4		0.17
MVP		0.47
MPC		0.32
ClinPred		0.22	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.24
Mutation Taster		=89/11	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: rs757892846; hg19: chr21-44448961;