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):ā€‹c.65T>Cā€‹(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: š‘“ 0.00093 ( 0 hom., cov: 33)
Exomes š‘“: 0.000096 ( 0 hom. )

Consequence

GNPAT
NM_014236.4 missense

Scores

1
18

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]

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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 UniProt
GNPATNM_014236.4 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant 1/16 ENST00000366647.9
GNPATNM_001316350.2 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant 1/15
GNPATXM_005273313.5 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant 1/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GNPATENST00000366647.9 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant 1/161 NM_014236.4 P1O15228-1
GNPATENST00000416000.1 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant 1/135
GNPATENST00000436239.5 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant 1/63
GNPATENST00000644483.1 linkuse as main transcriptc.65T>C p.Val22Ala missense_variant, NMD_transcript_variant 1/17

Frequencies

GnomAD3 genomes
AF:
0.000933
AC:
142
AN:
152188
Hom.:
0
Cov.:
33
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:
58
AN:
248992
Hom.:
0
AF XY:
0.000171
AC XY:
23
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.:
0
Cov.:
31
AF XY:
0.0000798
AC XY:
58
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.:
0
Cov.:
33
AF XY:
0.000806
AC XY:
60
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.:
0
Bravo
AF:
0.00120
ESP6500AA
AF:
0.00272
AC:
12
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000354
AC:
43

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 submitterclinical testingGeneDxDec 21, 2021- -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 19, 2024- -
Rhizomelic chondrodysplasia punctata type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 28, 2019The 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
T
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
N
LIST_S2
Benign
0.18
T;T;T
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.0049
T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.0
.;L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.50
T
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
T
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.

Other links and lift over

dbSNP: rs143388851; hg19: chr1-231377189; API