rs199905093

chr1-231265278-TC-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_014236.4(GNPAT):c.569-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,588,012 control chromosomes in the GnomAD database, including 125 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 33)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: GNPAT NM_014236.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.380

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 -9 ACMG points.

• BP6: Variant 1-231265278-TC-T is Benign according to our data. Variant chr1-231265278-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211091.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr1-231265278-TC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00822 (1252/152320) while in subpopulation NFE AF= 0.0115 (784/68016). AF 95% confidence interval is 0.0109. There are 12 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.569-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366647.9
GNPAT	NM_001316350.2	c.386-11del		splice_polypyrimidine_tract_variant, intron_variant
GNPAT	XM_005273313.5	c.566-11del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.569-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.539-11del		splice_polypyrimidine_tract_variant, intron_variant		5
GNPAT	ENST00000436239.5	c.386-11del		splice_polypyrimidine_tract_variant, intron_variant		3
GNPAT	ENST00000644483.1	c.*255-11del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1251 AN: 152202 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0101 AC: 2538 AN: 251074 Hom.: 22 AF XY: 0.0105 AC XY: 1433 AN XY: 135864

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00391

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00989

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0105 AC: 15127 AN: 1435692 Hom.: 113 Cov.: 28 AF XY: 0.0106 AC XY: 7596 AN XY: 716250

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.00511

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00896

GnomAD4 genome AF: 0.00822 AC: 1252 AN: 152320 Hom.: 12 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74482

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00385

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0111 Hom.: 1

Bravo AF: 0.00735

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	GNPAT: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 21, 2014

- -

Rhizomelic chondrodysplasia punctata type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs199905093; hg19: chr1-231401024;