1-231272345-A-G

Variant names:

• chr1-231272345-A-G
• rs11558492
• NM_014236.4:c.1556A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014236.4(GNPAT):​c.1556A>G​(p.Asp519Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,586,152 control chromosomes in the GnomAD database, including 32,140 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D519V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2241 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29899 hom.)
• Consequence: GNPAT NM_014236.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 1.92
• Publications: 61 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00137496).
• BP6: Variant 1-231272345-A-G is Benign according to our data. Variant chr1-231272345-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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.1556A>G	p.Asp519Gly	missense	Exon 11 of 16	NP_055051.1	O15228-1
	GNPAT	NM_001316350.2		c.1373A>G	p.Asp458Gly	missense	Exon 10 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.1556A>G	p.Asp519Gly	missense	Exon 11 of 16	ENSP00000355607.4	O15228-1
	GNPAT	ENST00000851685.1		c.1589A>G	p.Asp530Gly	missense	Exon 11 of 16	ENSP00000521744.1
	GNPAT	ENST00000926541.1		c.1556A>G	p.Asp519Gly	missense	Exon 11 of 16	ENSP00000596600.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24361 AN: 152082 Hom.: 2241 Cov.: 32

Gnomad AFR AF: 0.0926

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.163 AC: 41038 AN: 251422 AF XY: 0.168

Gnomad AFR exome AF: 0.0916

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0814

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.197 AC: 282758 AN: 1433952 Hom.: 29899 Cov.: 25 AF XY: 0.197 AC XY: 140778 AN XY: 714988

African (AFR) AF: 0.0911 AC: 3017 AN: 33116

American (AMR) AF: 0.124 AC: 5536 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5587 AN: 25890

East Asian (EAS) AF: 0.102 AC: 4048 AN: 39498

South Asian (SAS) AF: 0.149 AC: 12758 AN: 85660

European-Finnish (FIN) AF: 0.0841 AC: 4471 AN: 53150

Middle Eastern (MID) AF: 0.213 AC: 1217 AN: 5706

European-Non Finnish (NFE) AF: 0.216 AC: 234377 AN: 1086994

Other (OTH) AF: 0.198 AC: 11747 AN: 59332

GnomAD4 genome AF: 0.160 AC: 24369 AN: 152200 Hom.: 2241 Cov.: 32 AF XY: 0.152 AC XY: 11348 AN XY: 74430

African (AFR) AF: 0.0925 AC: 3844 AN: 41544

American (AMR) AF: 0.176 AC: 2686 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3470

East Asian (EAS) AF: 0.109 AC: 566 AN: 5172

South Asian (SAS) AF: 0.157 AC: 755 AN: 4818

European-Finnish (FIN) AF: 0.0790 AC: 839 AN: 10618

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14255 AN: 67988

Other (OTH) AF: 0.202 AC: 425 AN: 2102

Alfa AF: 0.198 Hom.: 12274

Bravo AF: 0.166

TwinsUK AF: 0.214 AC: 794

ALSPAC AF: 0.221 AC: 850

ESP6500AA AF: 0.0917 AC: 404

ESP6500EA AF: 0.206 AC: 1770

ExAC AF: 0.161 AC: 19576

Asia WGS AF: 0.116 AC: 401 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.227

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	5	Rhizomelic chondrodysplasia punctata type 2 (6)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.093
Sift	Benign	0.11	T
Sift4G	Benign	0.23	T
Polyphen		0.019	B
Vest4		0.13
MPC		0.35
ClinPred		0.011	T
GERP RS		-0.26
Varity_R		0.070
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

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: rs11558492; hg19: chr1-231408091; COSMIC: COSV64152997; COSMIC: COSV64152997;