1-231272345-A-T

Position:

• chr1-231272345-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014236.4(GNPAT):​c.1556A>T​(p.Asp519Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,296 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D519G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNPAT NM_014236.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPAT	NM_014236.4	c.1556A>T	p.Asp519Val	missense_variant	11/16	ENST00000366647.9
GNPAT	NM_001316350.2	c.1373A>T	p.Asp458Val	missense_variant	10/15
GNPAT	XM_005273313.5	c.1553A>T	p.Asp518Val	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPAT	ENST00000366647.9	c.1556A>T	p.Asp519Val	missense_variant	11/16	1	NM_014236.4	P1
GNPAT	ENST00000416000.1	c.1526A>T	p.Asp509Val	missense_variant	11/13	5
GNPAT	ENST00000644483.1	c.*1242A>T		3_prime_UTR_variant, NMD_transcript_variant	12/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440296 Hom.: 0 Cov.: 25 AF XY: 0.00000139 AC XY: 1 AN XY: 717974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.79	D;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.042	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.20
Sift	Benign	0.070	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.044	B;.
Vest4		0.44
MutPred		0.52		Loss of catalytic residue at D519 (P = 0.3098);.;
MVP		0.57
MPC		0.48
ClinPred		0.83	D
GERP RS		-0.26
Varity_R		0.16
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11558492; hg19: chr1-231408091;