8-96273366-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014754.3(PTDSS1):c.247A>C(p.Ile83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I83T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTDSS1 NM_014754.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

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]

LOC105375652 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25914633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTDSS1	NM_014754.3	c.247A>C	p.Ile83Leu	missense_variant	2/13	ENST00000517309.6
LOC105375652	XR_928431.3	n.91-7029T>G		intron_variant, non_coding_transcript_variant
PTDSS1	NM_001290225.2	c.-22A>C		5_prime_UTR_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTDSS1	ENST00000517309.6	c.247A>C	p.Ile83Leu	missense_variant	2/13	1	NM_014754.3	P1
PTDSS1	ENST00000337004.8	c.247A>C	p.Ile83Leu	missense_variant, NMD_transcript_variant	2/11	1
PTDSS1	ENST00000517557.5	n.321A>C		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lenz-Majewski hyperostosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 03, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Sift4G	Benign	0.11	T
Polyphen		0.024	B
Vest4		0.47
MutPred		0.32		Loss of sheet (P = 0.0457);
MVP		0.23
MPC		0.66
ClinPred		0.91	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs1810593860; hg19: chr8-97285594;