chr8-96273388-A-G

Position:

chr8-96273388-A-G

Variant summary

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

The NM_001290225.2(PTDSS1):c.1A>G(p.Met1?) variant causes a start lost, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,450,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTDSS1
NM_001290225.2 start_lost, splice_region

Scores

Splicing: ADA: 0.6937

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

PTDSS1 (HGNC:9587): (phosphatidylserine synthase 1) The protein encoded by this gene catalyzes the formation of phosphatidylserine from either phosphatidylcholine or phosphatidylethanolamine. Phosphatidylserine localizes to the mitochondria-associated membrane of the endoplasmic reticulum, where it serves a structural role as well as a signaling role. Defects in this gene are a cause of Lenz-Majewski hyperostotic dwarfism. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

PTDSS1 links:

PTDSS1 (HGNC:):

PTDSS1 links:

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ACMG classification

Classification made for transcript

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
PTDSS1	NM_014754.3 linkuse as main transcript	c.269A>G	p.Asn90Ser	missense_variant, splice_region_variant	2/13	ENST00000517309.6	NP_055569.1	P48651-1
PTDSS1	NM_001290225.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost, splice_region_variant	2/11		NP_001277154.1	P48651-2
LOC105375652	XR_928431.3 linkuse as main transcript	n.91-7051T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PTDSS1	ENST00000517309.6 linkuse as main transcript	c.269A>G	p.Asn90Ser	missense_variant, splice_region_variant	2/13	1	NM_014754.3	ENSP00000430548.1	P48651-1
PTDSS1	ENST00000337004.8 linkuse as main transcript	n.269A>G		splice_region_variant, non_coding_transcript_exon_variant	2/11	1		ENSP00000337331.4	J3KNR6
PTDSS1	ENST00000517557.5 linkuse as main transcript	n.343A>G		splice_region_variant, non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245462

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450554

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

722012

show subpopulations

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 90 of the PTDSS1 protein (p.Asn90Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PTDSS1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.029

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.26

Sift

Uncertain

0.019

Sift4G

Benign

0.092

Polyphen

0.22

Vest4

0.55

MutPred

0.41

Gain of glycosylation at N90 (P = 0.0016);

MVP

0.41

MPC

0.56

ClinPred

0.87

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.69

dbscSNV1_RF

Benign

0.55

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over