rs6659098

chr1-231262809-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014236.4(GNPAT):c.525A>G(p.Leu175=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,610,468 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: GNPAT NM_014236.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.44

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=-0.9).
• BP6: Variant 1-231262809-A-G is Benign according to our data. Variant chr1-231262809-A-G is described in ClinVar as [Benign]. Clinvar id is 260362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00952 (1450/152308) while in subpopulation AFR AF= 0.0326 (1354/41558). AF 95% confidence interval is 0.0311. There are 22 homozygotes in gnomad4. There are 683 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.525A>G	p.Leu175=	synonymous_variant	4/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.342A>G	p.Leu114=	synonymous_variant	3/15
GNPAT	XM_005273313.5	c.522A>G	p.Leu174=	synonymous_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.525A>G	p.Leu175=	synonymous_variant	4/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.495A>G	p.Leu165=	synonymous_variant	4/13	5
GNPAT	ENST00000436239.5	c.342A>G	p.Leu114=	synonymous_variant	3/6	3
GNPAT	ENST00000644483.1	c.*211A>G		3_prime_UTR_variant, NMD_transcript_variant	5/17

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1447 AN: 152190 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00275 AC: 690 AN: 251364 Hom.: 14 AF XY: 0.00220 AC XY: 299 AN XY: 135854

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00117 AC: 1713 AN: 1458160 Hom.: 30 Cov.: 29 AF XY: 0.00114 AC XY: 828 AN XY: 725706

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00236

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00952 AC: 1450 AN: 152308 Hom.: 22 Cov.: 32 AF XY: 0.00917 AC XY: 683 AN XY: 74462

Gnomad4 AFR AF: 0.0326

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00651 Hom.: 6

Bravo AF: 0.0101

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2017	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	-	- -

Rhizomelic chondrodysplasia punctata type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.11
Dann	Benign	0.35

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: rs6659098; hg19: chr1-231398555;