Genetic Variant NM_014754.3:c.805C>T (chr8-96304092-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_014754.3(PTDSS1):c.805C>T(p.Pro269Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P269L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTDSS1
NM_014754.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.90

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Lenz-Majewski hyperostotic dwarfism
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

PTDSS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-96304093-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3777039.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 8-96304092-C-T is Pathogenic according to our data. Variant chr8-96304092-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 97035.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014754.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTDSS1	NM_014754.3	MANE Select	c.805C>T	p.Pro269Ser	missense	Exon 7 of 13	NP_055569.1
	PTDSS1	NM_001290225.2		c.367C>T	p.Pro123Ser	missense	Exon 5 of 11	NP_001277154.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTDSS1	ENST00000517309.6	TSL:1 MANE Select	c.805C>T	p.Pro269Ser	missense	Exon 7 of 13	ENSP00000430548.1
PTDSS1	ENST00000337004.8	TSL:1	n.*308C>T		non_coding_transcript_exon	Exon 5 of 11	ENSP00000337331.4
PTDSS1	ENST00000337004.8	TSL:1	n.*308C>T		3_prime_UTR	Exon 5 of 11	ENSP00000337331.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Lenz-Majewski hyperostosis syndrome

Pathogenic:1

Jan 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.5

PhyloP100

7.9

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.94

Gain of MoRF binding (P = 0.0336)

MVP

0.72

MPC

1.7

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over