NM_014236.4:c.525A>G

Variant names:

• chr1-231262809-A-G
• rs6659098
• NM_014236.4:c.525A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014236.4(GNPAT):​c.525A>G​(p.Leu175Leu) 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:6
• Conservation: PhyloP100: -1.44
• 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	NM_014236.4	MANE Select	c.525A>G	p.Leu175Leu	synonymous	Exon 4 of 16	NP_055051.1	O15228-1
	GNPAT	NM_001316350.2		c.342A>G	p.Leu114Leu	synonymous	Exon 3 of 15	NP_001303279.1	O15228-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	ENST00000366647.9	TSL:1 MANE Select	c.525A>G	p.Leu175Leu	synonymous	Exon 4 of 16	ENSP00000355607.4	O15228-1
	GNPAT	ENST00000851685.1		c.558A>G	p.Leu186Leu	synonymous	Exon 4 of 16	ENSP00000521744.1
	GNPAT	ENST00000926541.1		c.525A>G	p.Leu175Leu	synonymous	Exon 4 of 16	ENSP00000596600.1

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

GnomAD2 exomes AF: 0.00275 AC: 690 AN: 251364 AF XY: 0.00220

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 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

African (AFR) AF: 0.0318 AC: 1062 AN: 33392

American (AMR) AF: 0.00224 AC: 100 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00236 AC: 203 AN: 86184

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53400

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1108674

Other (OTH) AF: 0.00219 AC: 132 AN: 60242

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

African (AFR) AF: 0.0326 AC: 1354 AN: 41558

American (AMR) AF: 0.00314 AC: 48 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00551 Hom.: 10

Bravo AF: 0.0101

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.35
PhyloP100		-1.4
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: rs6659098; hg19: chr1-231398555;