1-231241401-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014236.4(GNPAT):c.23A>G(p.Asn8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPAT NM_014236.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0880

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081698895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.23A>G	p.Asn8Ser	missense_variant	1/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.23A>G	p.Asn8Ser	missense_variant	1/15
GNPAT	XM_005273313.5	c.23A>G	p.Asn8Ser	missense_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.23A>G	p.Asn8Ser	missense_variant	1/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.23A>G	p.Asn8Ser	missense_variant	1/13	5
GNPAT	ENST00000436239.5	c.23A>G	p.Asn8Ser	missense_variant	1/6	3
GNPAT	ENST00000644483.1	c.23A>G	p.Asn8Ser	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2021

This sequence change replaces asparagine with serine at codon 8 of the GNPAT protein (p.Asn8Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GNPAT-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	0.18
Dann	Benign	0.80
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.14	N;N;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.0	.;B;.
Vest4		0.16
MutPred		0.20		Gain of phosphorylation at N8 (P = 0.0042);Gain of phosphorylation at N8 (P = 0.0042);Gain of phosphorylation at N8 (P = 0.0042);
MVP		0.70
MPC		0.18
ClinPred		0.16	T
GERP RS		-1.8
Varity_R		0.077
gMVP		0.26

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: chr1-231377147;