rs121434440

Positions:

• chr1-231265355-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000366647.9(GNPAT):​c.631C>T​(p.Arg211Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GNPAT ENST00000366647.9 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.77

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-231265356-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-231265355-C-T is Pathogenic according to our data. Variant chr1-231265355-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231265355-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPAT	NM_014236.4	c.631C>T	p.Arg211Cys	missense_variant	5/16	ENST00000366647.9	NP_055051.1
GNPAT	NM_001316350.2	c.448C>T	p.Arg150Cys	missense_variant	4/15		NP_001303279.1
GNPAT	XM_005273313.5	c.628C>T	p.Arg210Cys	missense_variant	5/16		XP_005273370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPAT	ENST00000366647.9	c.631C>T	p.Arg211Cys	missense_variant	5/16	1	NM_014236.4	ENSP00000355607	P1
GNPAT	ENST00000416000.1	c.601C>T	p.Arg201Cys	missense_variant	5/13	5		ENSP00000411640
GNPAT	ENST00000436239.5	c.448C>T	p.Arg150Cys	missense_variant	4/6	3		ENSP00000402811
GNPAT	ENST00000644483.1	c.*317C>T		3_prime_UTR_variant, NMD_transcript_variant	6/17			ENSP00000496537

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251464 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457372 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 725404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 15, 2023	- -

Rhizomelic chondrodysplasia punctata Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 22, 2023

Variant summary: GNPAT c.631C>T (p.Arg211Cys) results in a non-conservative amino acid change located in the Phospholipid/glycerol acyltransferase (IPR002123) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes. c.631C>T has been reported in the literature in individuals affected with Rhizomelic Chondrodysplasia Punctata (Ofman_2001). At least one publication reports experimental evidence evaluating an impact on protein function indicating no GNPAT enzyme activity in a homozygous individual (Ofman_2001). Another variant affecting the same amino acid (p.Arg211His, pathogenic in ClinVar) has been observed in homozygous individuals with no GNPAT activity suggesting an important role of this variant in disease. The following publication have been ascertained in the context of this evaluation (PMID: 11237722).No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.99		.;Loss of MoRF binding (P = 0.0124);.;
MVP		0.94
MPC		1.0
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.90
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121434440; hg19: chr1-231401101;