rs193920851

Positions:

• chr1-231275496-G-C

Variant summary

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

The NM_014236.4(GNPAT):​c.1935G>C​(p.Lys645Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNPAT NM_014236.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003660
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.20

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	Protein	UniProt
GNPAT	NM_014236.4	c.1935G>C	p.Lys645Asn	missense_variant, splice_region_variant	14/16	ENST00000366647.9	NP_055051.1
GNPAT	NM_001316350.2	c.1752G>C	p.Lys584Asn	missense_variant, splice_region_variant	13/15		NP_001303279.1
GNPAT	XM_005273313.5	c.1932G>C	p.Lys644Asn	missense_variant, splice_region_variant	14/16		XP_005273370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPAT	ENST00000366647.9	c.1935G>C	p.Lys645Asn	missense_variant, splice_region_variant	14/16	1	NM_014236.4	ENSP00000355607	P1
GNPAT	ENST00000469332.1	n.517G>C		splice_region_variant, non_coding_transcript_exon_variant	2/4	2
GNPAT	ENST00000644483.1	c.*1621G>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	15/17			ENSP00000496537

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.64	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.49		Loss of catalytic residue at K645 (P = 0.0057);
MVP		0.70
MPC		0.74
ClinPred		0.96	D
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.24
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.094
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: rs193920851; hg19: chr1-231411242; COSMIC: COSV64154583; COSMIC: COSV64154583;