1-231272345-A-G

Variant names:

• chr1-231272345-A-G
• rs11558492
• NM_014236.4:c.1556A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014236.4(GNPAT):​c.1556A>G​(p.Asp519Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,586,152 control chromosomes in the GnomAD database, including 32,140 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2241 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29899 hom.)
• Consequence: GNPAT NM_014236.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 1.92
• Publications: 61 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00137496).
• BP6: Variant 1-231272345-A-G is Benign according to our data. Variant chr1-231272345-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPAT	NM_014236.4	c.1556A>G	p.Asp519Gly	missense_variant	Exon 11 of 16	ENST00000366647.9	NP_055051.1
GNPAT	NM_001316350.2	c.1373A>G	p.Asp458Gly	missense_variant	Exon 10 of 15		NP_001303279.1
GNPAT	XM_005273313.5	c.1553A>G	p.Asp518Gly	missense_variant	Exon 11 of 16		XP_005273370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPAT	ENST00000366647.9	c.1556A>G	p.Asp519Gly	missense_variant	Exon 11 of 16	1	NM_014236.4	ENSP00000355607.4
GNPAT	ENST00000416000.1	c.1526A>G	p.Asp509Gly	missense_variant	Exon 11 of 13	5		ENSP00000411640.1
GNPAT	ENST00000644483.1	n.*1242A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000496537.1
GNPAT	ENST00000644483.1	n.*1242A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000496537.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24361 AN: 152082 Hom.: 2241 Cov.: 32

Gnomad AFR AF: 0.0926

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.163 AC: 41038 AN: 251422 AF XY: 0.168

Gnomad AFR exome AF: 0.0916

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0814

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.197 AC: 282758 AN: 1433952 Hom.: 29899 Cov.: 25 AF XY: 0.197 AC XY: 140778 AN XY: 714988

African (AFR) AF: 0.0911 AC: 3017 AN: 33116

American (AMR) AF: 0.124 AC: 5536 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5587 AN: 25890

East Asian (EAS) AF: 0.102 AC: 4048 AN: 39498

South Asian (SAS) AF: 0.149 AC: 12758 AN: 85660

European-Finnish (FIN) AF: 0.0841 AC: 4471 AN: 53150

Middle Eastern (MID) AF: 0.213 AC: 1217 AN: 5706

European-Non Finnish (NFE) AF: 0.216 AC: 234377 AN: 1086994

Other (OTH) AF: 0.198 AC: 11747 AN: 59332

GnomAD4 genome AF: 0.160 AC: 24369 AN: 152200 Hom.: 2241 Cov.: 32 AF XY: 0.152 AC XY: 11348 AN XY: 74430

African (AFR) AF: 0.0925 AC: 3844 AN: 41544

American (AMR) AF: 0.176 AC: 2686 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3470

East Asian (EAS) AF: 0.109 AC: 566 AN: 5172

South Asian (SAS) AF: 0.157 AC: 755 AN: 4818

European-Finnish (FIN) AF: 0.0790 AC: 839 AN: 10618

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14255 AN: 67988

Other (OTH) AF: 0.202 AC: 425 AN: 2102

Alfa AF: 0.198 Hom.: 12274

Bravo AF: 0.166

TwinsUK AF: 0.214 AC: 794

ALSPAC AF: 0.221 AC: 850

ESP6500AA AF: 0.0917 AC: 404

ESP6500EA AF: 0.206 AC: 1770

ExAC AF: 0.161 AC: 19576

Asia WGS AF: 0.116 AC: 401 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.227

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 2 Pathogenic:1 Benign:5

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Benign:3

Mar 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 22, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.093
Sift	Benign	0.11	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.019	B;.
Vest4		0.13
MPC		0.35
ClinPred		0.011	T
GERP RS		-0.26
Varity_R		0.070
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11558492; hg19: chr1-231408091; COSMIC: COSV64152997; COSMIC: COSV64152997;