Genetic Variant GNPAT:p.Lys645Asn (chr1-231275496-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014236.4(GNPAT):c.1935G>C(p.Lys645Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K645M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GNPAT
NM_014236.4 missense, splice_region

Scores

Splicing: ADA: 0.00003660

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.20

Publications

0 publications found

Variant links:

Genes affected

GNPAT (HGNC:4416): (glyceronephosphate O-acyltransferase) This gene encodes an enzyme located in the peroxisomal membrane which is essential to the synthesis of ether phospholipids. Mutations in this gene are associated with rhizomelic chondrodysplasia punctata. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

GNPAT Gene-Disease associations (from GenCC):

glyceronephosphate O-acyltransferase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
rhizomelic chondrodysplasia punctata type 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

GNPAT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014236.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	NM_014236.4	MANE Select	c.1935G>C	p.Lys645Asn	missense splice_region	Exon 14 of 16	NP_055051.1
	GNPAT	NM_001316350.2		c.1752G>C	p.Lys584Asn	missense splice_region	Exon 13 of 15	NP_001303279.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNPAT	ENST00000366647.9	TSL:1 MANE Select	c.1935G>C	p.Lys645Asn	missense splice_region	Exon 14 of 16	ENSP00000355607.4
GNPAT	ENST00000469332.1	TSL:2	n.517G>C		splice_region non_coding_transcript_exon	Exon 2 of 4
GNPAT	ENST00000644483.1		n.*1621G>C		splice_region non_coding_transcript_exon	Exon 15 of 17	ENSP00000496537.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Prostate cancer

Uncertain:1

Science for Life laboratory, Karolinska Institutet

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.81

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

PhyloP100

1.2

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.24

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.60

MutPred

0.49

Loss of catalytic residue at K645 (P = 0.0057)

MVP

0.70

MPC

0.74

ClinPred

0.96

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.24

gMVP

0.51

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.094

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over