rs574553

chr1-231266156-G-Achr1-231266156-G-Cchr1-231266156-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014236.4(GNPAT):c.915G>A(p.Glu305=) 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:7
• Conservation: PhyloP100: 1.63

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 -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 ClinVar 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 Lovd as [Benign].
• 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/exons	MANE	UniProt
GNPAT	NM_014236.4	c.915G>A	p.Glu305=	synonymous_variant	7/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.732G>A	p.Glu244=	synonymous_variant	6/15
GNPAT	XM_005273313.5	c.912G>A	p.Glu304=	synonymous_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.915G>A	p.Glu305=	synonymous_variant	7/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.885G>A	p.Glu295=	synonymous_variant	7/13	5
GNPAT	ENST00000492459.1	n.23G>A		non_coding_transcript_exon_variant	1/4	2
GNPAT	ENST00000644483.1	c.*601G>A		3_prime_UTR_variant, NMD_transcript_variant	8/17

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

GnomAD3 exomes AF: 0.570 AC: 143156 AN: 251224 Hom.: 41427 AF XY: 0.569 AC XY: 77275 AN XY: 135816

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 SAS exome AF: 0.625

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

Gnomad4 AFR exome AF: 0.691

Gnomad4 AMR exome AF: 0.613

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.606

Gnomad4 SAS exome AF: 0.621

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.577

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

Gnomad4 AFR AF: 0.690

Gnomad4 AMR AF: 0.608

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.605

Alfa AF: 0.569 Hom.: 18055

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 2 Benign:3

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	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.5
Dann	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs574553; hg19: chr1-231401902; COSMIC: COSV64153484; COSMIC: COSV64153484;