rs199905093

Variant names:

• chr1-231265278-TC-T
• rs199905093
• NM_014236.4:c.569-11delC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_014236.4(GNPAT):​c.569-11delC variant causes a 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.380
• Publications: 1 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 -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 VariationId is 211091.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014236.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	NM_014236.4	MANE Select	c.569-11delC		intron	N/A	NP_055051.1
	GNPAT	NM_001316350.2		c.386-11delC		intron	N/A	NP_001303279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	ENST00000366647.9	TSL:1 MANE Select	c.569-14delC		intron	N/A	ENSP00000355607.4
	GNPAT	ENST00000416000.1	TSL:5	c.539-14delC		intron	N/A	ENSP00000411640.1
	GNPAT	ENST00000436239.5	TSL:3	c.386-14delC		intron	N/A	ENSP00000402811.1

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

GnomAD2 exomes AF: 0.0101 AC: 2538 AN: 251074 AF XY: 0.0105

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 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

African (AFR) AF: 0.00164 AC: 54 AN: 33004

American (AMR) AF: 0.00338 AC: 151 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 449 AN: 25972

East Asian (EAS) AF: 0.00511 AC: 202 AN: 39562

South Asian (SAS) AF: 0.0118 AC: 1011 AN: 85748

European-Finnish (FIN) AF: 0.0117 AC: 624 AN: 53388

Middle Eastern (MID) AF: 0.00332 AC: 19 AN: 5730

European-Non Finnish (NFE) AF: 0.0111 AC: 12083 AN: 1088000

Other (OTH) AF: 0.00896 AC: 534 AN: 59600

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

African (AFR) AF: 0.00195 AC: 81 AN: 41588

American (AMR) AF: 0.00556 AC: 85 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3468

East Asian (EAS) AF: 0.00385 AC: 20 AN: 5190

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4824

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 784 AN: 68016

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.0111 Hom.: 1

Bravo AF: 0.00735

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	not specified (1)
-	-	1	Rhizomelic chondrodysplasia punctata type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199905093; hg19: chr1-231401024;