chr1-231272345-A-G

Position:

• chr1-231272345-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:9
• Conservation: PhyloP100: 1.92

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 35465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231272345-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
GNPAT	NM_014236.4	c.1556A>G	p.Asp519Gly	missense_variant	11/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.1373A>G	p.Asp458Gly	missense_variant	10/15
GNPAT	XM_005273313.5	c.1553A>G	p.Asp518Gly	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.1556A>G	p.Asp519Gly	missense_variant	11/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.1526A>G	p.Asp509Gly	missense_variant	11/13	5
GNPAT	ENST00000644483.1	c.*1242A>G		3_prime_UTR_variant, NMD_transcript_variant	12/17

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

GnomAD3 exomes AF: 0.163 AC: 41038 AN: 251422 Hom.: 3656 AF XY: 0.168 AC XY: 22891 AN XY: 135878

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 SAS exome AF: 0.154

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

Gnomad4 AFR exome AF: 0.0911

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.0841

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.198

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

Gnomad4 AFR AF: 0.0925

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0790

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.202

Alfa AF: 0.206 Hom.: 8654

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 2 Pathogenic:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1998	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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;.
MutationTaster	Benign	1.0	P;P
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

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

LitVar

Other links and lift over

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