chr1-231241226-A-C

Variant names:

• chr1-231241226-A-C
• rs537119013
• NM_014236.4:c.-153A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_014236.4(GNPAT):​c.-153A>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000292 in 1,504,834 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (5 hom.)
• Consequence: GNPAT NM_014236.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 publications found

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]

FSAF1 (HGNC:25332): (chromosome 1 open reading frame 131) Enables RNA binding activity. Located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000118 (18/152334) while in subpopulation EAS AF = 0.00348 (18/5178). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014236.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	NM_014236.4	MANE Select	c.-153A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_055051.1	O15228-1
	GNPAT	NM_014236.4	MANE Select	c.-153A>C		5_prime_UTR	Exon 1 of 16	NP_055051.1	O15228-1
	GNPAT	NM_001316350.2		c.-153A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001303279.1	O15228-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPAT	ENST00000366647.9	TSL:1 MANE Select	c.-153A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000355607.4	O15228-1
	GNPAT	ENST00000366647.9	TSL:1 MANE Select	c.-153A>C		5_prime_UTR	Exon 1 of 16	ENSP00000355607.4	O15228-1
	GNPAT	ENST00000851685.1		c.-153A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000521744.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000312 AC: 422 AN: 1352500 Hom.: 5 Cov.: 22 AF XY: 0.000332 AC XY: 225 AN XY: 677212

African (AFR) AF: 0.00 AC: 0 AN: 31022

American (AMR) AF: 0.00 AC: 0 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24746

East Asian (EAS) AF: 0.0106 AC: 415 AN: 39080

South Asian (SAS) AF: 0.00 AC: 0 AN: 83484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4760

European-Non Finnish (NFE) AF: 9.84e-7 AC: 1 AN: 1016356

Other (OTH) AF: 0.000106 AC: 6 AN: 56528

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Rhizomelic chondrodysplasia punctata type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.88
PhyloP100		4.0
PromoterAI		-0.59	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=289/11	polymorphism

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

Other links and lift over

dbSNP: rs537119013; hg19: chr1-231376972;