NM_014236.4:c.915G>A

Variant names:

• chr1-231266156-G-A
• rs574553
• NM_014236.4:c.915G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014236.4(GNPAT):​c.915G>A​(p.Glu305Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 1,611,462 control chromosomes in the GnomAD database, including 260,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26814 hom., cov: 32)
  • Exomes 𝑓: 0.56 (233392 hom.)
• Consequence: GNPAT NM_014236.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.63
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-231266156-G-A is Benign according to our data. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231266156-G-A is described in CliVar as Benign. Clinvar id is 260363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPAT	NM_014236.4	c.915G>A	p.Glu305Glu	synonymous_variant	Exon 7 of 16	ENST00000366647.9	NP_055051.1
GNPAT	NM_001316350.2	c.732G>A	p.Glu244Glu	synonymous_variant	Exon 6 of 15		NP_001303279.1
GNPAT	XM_005273313.5	c.912G>A	p.Glu304Glu	synonymous_variant	Exon 7 of 16		XP_005273370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPAT	ENST00000366647.9	c.915G>A	p.Glu305Glu	synonymous_variant	Exon 7 of 16	1	NM_014236.4	ENSP00000355607.4

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89380 AN: 151934 Hom.: 26756 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.570 AC: 143156 AN: 251224 AF XY: 0.569

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.597

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.563 AC: 821393 AN: 1459410 Hom.: 233392 Cov.: 37 AF XY: 0.564 AC XY: 409864 AN XY: 726186

African (AFR) AF: 0.691 AC: 23098 AN: 33434

American (AMR) AF: 0.613 AC: 27395 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 15963 AN: 26118

East Asian (EAS) AF: 0.606 AC: 24056 AN: 39688

South Asian (SAS) AF: 0.621 AC: 53582 AN: 86218

European-Finnish (FIN) AF: 0.444 AC: 23586 AN: 53164

Middle Eastern (MID) AF: 0.527 AC: 3035 AN: 5760

European-Non Finnish (NFE) AF: 0.555 AC: 615877 AN: 1109990

Other (OTH) AF: 0.577 AC: 34801 AN: 60316

GnomAD4 genome AF: 0.589 AC: 89487 AN: 152052 Hom.: 26814 Cov.: 32 AF XY: 0.584 AC XY: 43381 AN XY: 74322

African (AFR) AF: 0.690 AC: 28621 AN: 41484

American (AMR) AF: 0.608 AC: 9292 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2177 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3214 AN: 5178

South Asian (SAS) AF: 0.621 AC: 2991 AN: 4820

European-Finnish (FIN) AF: 0.434 AC: 4570 AN: 10534

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36785 AN: 67974

Other (OTH) AF: 0.605 AC: 1275 AN: 2108

Alfa AF: 0.570 Hom.: 19991

Bravo AF: 0.605

Asia WGS AF: 0.619 AC: 2154 AN: 3478

EpiCase AF: 0.554

EpiControl AF: 0.554

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 2 Benign:3

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. -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: 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

- -

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.5
DANN	Benign	0.31
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs574553; hg19: chr1-231401902; COSMIC: COSV64153484; COSMIC: COSV64153484;