chr1-231262767-T-G

Position:

• chr1-231262767-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014236.4(GNPAT):​c.483T>G​(p.Ser161Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GNPAT NM_014236.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.578

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.483T>G	p.Ser161Arg	missense_variant	4/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.300T>G	p.Ser100Arg	missense_variant	3/15
GNPAT	XM_005273313.5	c.480T>G	p.Ser160Arg	missense_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.483T>G	p.Ser161Arg	missense_variant	4/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.453T>G	p.Ser151Arg	missense_variant	4/13	5
GNPAT	ENST00000436239.5	c.300T>G	p.Ser100Arg	missense_variant	3/6	3
GNPAT	ENST00000644483.1	c.*169T>G		3_prime_UTR_variant, NMD_transcript_variant	5/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251368 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454792 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 161 of the GNPAT protein (p.Ser161Arg). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with GNPAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 520699). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.93
MutPred		0.78		.;Gain of helix (P = 0.132);.;
MVP		0.91
MPC		0.90
ClinPred		0.97	D
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1259353676; hg19: chr1-231398513;