rs34613633

chr1-231262839-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014236.4(GNPAT):c.555A>T(p.Ile185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,612,240 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (17 hom.)
• Consequence: GNPAT NM_014236.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.429

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-231262839-A-T is Benign according to our data. Variant chr1-231262839-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211090.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr1-231262839-A-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.429 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00319 (486/152356) while in subpopulation NFE AF= 0.00503 (342/68032). AF 95% confidence interval is 0.00459. There are 2 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.555A>T	p.Ile185=	synonymous_variant	4/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.372A>T	p.Ile124=	synonymous_variant	3/15
GNPAT	XM_005273313.5	c.552A>T	p.Ile184=	synonymous_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.555A>T	p.Ile185=	synonymous_variant	4/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.525A>T	p.Ile175=	synonymous_variant	4/13	5
GNPAT	ENST00000436239.5	c.372A>T	p.Ile124=	synonymous_variant	3/6	3
GNPAT	ENST00000644483.1	c.*241A>T		3_prime_UTR_variant, NMD_transcript_variant	5/17

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152238 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00744

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00503

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00370 AC: 929 AN: 251274 Hom.: 4 AF XY: 0.00369 AC XY: 501 AN XY: 135806

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00662

Gnomad NFE exome AF: 0.00587

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00405 AC: 5917 AN: 1459884 Hom.: 17 Cov.: 29 AF XY: 0.00406 AC XY: 2949 AN XY: 726446

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00761

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152356 Hom.: 2 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74506

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00744

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00411 Hom.: 0

Bravo AF: 0.00247

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GNPAT: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Rhizomelic chondrodysplasia punctata type 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 21, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	8.0
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34613633; hg19: chr1-231398585;