1-231241443-T-C

Position:

chr1-231241443-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_014236.4(GNPAT):c.65T>C(p.Val22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V22V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

GNPAT
NM_014236.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.361

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0049017966).

BP6

Variant 1-231241443-T-C is Benign according to our data. Variant chr1-231241443-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 716279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000932 (142/152306) while in subpopulation AFR AF= 0.0033 (137/41568). AF 95% confidence interval is 0.00285. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GNPAT	NM_014236.4 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant	1/16	ENST00000366647.9
GNPAT	NM_001316350.2 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant	1/15
GNPAT	XM_005273313.5 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant	1/16	1	NM_014236.4	P1	O15228-1
GNPAT	ENST00000416000.1 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant	1/13	5
GNPAT	ENST00000436239.5 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant	1/6	3
GNPAT	ENST00000644483.1 linkuse as main transcript	c.65T>C	p.Val22Ala	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes

AF:

0.000933

AC:

142

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000233

AC:

AN:

248992

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

134794

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.000231

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:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000959

AC:

140

AN:

1460222

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.00335

Gnomad4 AMR exome

AF:

0.000291

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:

0.00000270

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000932

AC:

142

AN:

152306

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000200

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Rhizomelic chondrodysplasia punctata type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 28, 2019

The GNPAT c.65T>C; p.Val22Ala variant (rs143388851), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found in the African population with an overall allele frequency of 0.35% (87/24968 alleles) in the Genome Aggregation Database. The valine at codon 22 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Val22Ala variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

5.0

DANN

Benign

0.60

DEOGEN2

Benign

0.16

.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.18

T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.0

.;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.33

N;N;N

REVEL

Benign

0.090

Sift

Benign

0.57

T;D;D

Sift4G

Benign

0.57

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.083

MVP

0.54

MPC

0.28

ClinPred

0.010

GERP RS

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.028

gMVP

0.30

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over