1-231241335-C-T

Position:

• chr1-231241335-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014236.4(GNPAT):​c.-44C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,533,732 control chromosomes in the GnomAD database, including 236,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23102 hom., cov: 33)
  • Exomes 𝑓: 0.55 (213654 hom.)
• Consequence: GNPAT NM_014236.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.132

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-231241335-C-T is Benign according to our data. Variant chr1-231241335-C-T is described in ClinVar as [Benign]. Clinvar id is 296108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.-44C>T		5_prime_UTR_variant	1/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.-44C>T		5_prime_UTR_variant	1/15
GNPAT	XM_005273313.5	c.-44C>T		5_prime_UTR_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.-44C>T		5_prime_UTR_variant	1/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.-44C>T		5_prime_UTR_variant	1/13	5
GNPAT	ENST00000436239.5	c.-44C>T		5_prime_UTR_variant	1/6	3
GNPAT	ENST00000644483.1	c.-44C>T		5_prime_UTR_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83376 AN: 151936 Hom.: 23065 Cov.: 33

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.570

GnomAD3 exomes AF: 0.554 AC: 138395 AN: 249700 Hom.: 38910 AF XY: 0.556 AC XY: 75079 AN XY: 135086

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.594

Gnomad SAS exome AF: 0.624

Gnomad FIN exome AF: 0.434

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.553 AC: 764355 AN: 1381678 Hom.: 213654 Cov.: 22 AF XY: 0.555 AC XY: 384322 AN XY: 692114

Gnomad4 AFR exome AF: 0.566

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.598

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.549 AC: 83456 AN: 152054 Hom.: 23102 Cov.: 33 AF XY: 0.544 AC XY: 40466 AN XY: 74328

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.593

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.425

Gnomad4 NFE AF: 0.534

Gnomad4 OTH AF: 0.571

Alfa AF: 0.548 Hom.: 37357

Bravo AF: 0.561

Asia WGS AF: 0.605 AC: 2106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.7
DANN	Benign	0.70

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

Other links and lift over

dbSNP: rs518686; hg19: chr1-231377081; COSMIC: COSV59641814; COSMIC: COSV59641814;