10-89593820-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_148977.3(PANK1):​c.1069G>A​(p.Ala357Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PANK1
NM_148977.3 missense

Scores

15
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85
Variant links:
Genes affected
PANK1 (HGNC:8598): (pantothenate kinase 1) This gene encodes a member of the pantothenate kinase family. Pantothenate kinases are key regulatory enzymes in the biosynthesis of coenzyme A (CoA). The encoded protein catalyzes the first and rate-limiting enzymatic reaction in CoA biosynthesis and is regulated by CoA through feedback inhibition. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. This gene and an intronic miRNA on the same strand are co-regulated by the tumor suppressor p53 (see PMID 20833636). [provided by RefSeq, Apr 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PANK1NM_148977.3 linkc.1069G>A p.Ala357Thr missense_variant Exon 4 of 7 ENST00000307534.10 NP_683878.2 Q8TE04

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PANK1ENST00000307534.10 linkc.1069G>A p.Ala357Thr missense_variant Exon 4 of 7 1 NM_148977.3 ENSP00000302108.5 A0A8C8KBT8
PANK1ENST00000342512.4 linkc.805G>A p.Ala269Thr missense_variant Exon 4 of 7 1 ENSP00000345118.3 Q8TE04-2
PANK1ENST00000322191.10 linkc.636-500G>A intron_variant Intron 3 of 5 1 ENSP00000318526.6 Q8TE04-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1480G>A (p.A494T) alteration is located in exon 4 (coding exon 4) of the PANK1 gene. This alteration results from a G to A substitution at nucleotide position 1480, causing the alanine (A) at amino acid position 494 to be replaced by a threonine (T). 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
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.7
H;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.8
D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0090
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.96
MutPred
0.59
Gain of phosphorylation at A494 (P = 0.0926);.;
MVP
0.99
MPC
1.6
ClinPred
1.0
D
GERP RS
6.2
Varity_R
0.81
gMVP
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-91353577; API