8-96262138-C-T

Variant names:

• chr8-96262138-C-T
• rs751925742
• NM_014754.3:c.98C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014754.3(PTDSS1):​c.98C>T​(p.Thr33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,644 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. T33S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTDSS1 NM_014754.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 0 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTDSS1	NM_014754.3	MANE Select	c.98C>T	p.Thr33Ile	missense	Exon 1 of 13	NP_055569.1	P48651-1
	PTDSS1	NM_001290225.2		c.-171C>T		5_prime_UTR	Exon 1 of 11	NP_001277154.1	P48651-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTDSS1	ENST00000517309.6	TSL:1 MANE Select	c.98C>T	p.Thr33Ile	missense	Exon 1 of 13	ENSP00000430548.1	P48651-1
	PTDSS1	ENST00000337004.8	TSL:1	n.98C>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000337331.4	J3KNR6
	PTDSS1	ENST00000894612.1		c.98C>T	p.Thr33Ile	missense	Exon 1 of 14	ENSP00000564671.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251332 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.92	P
Vest4		0.51
MutPred		0.53		Loss of catalytic residue at T33 (P = 0.0276)
MVP		0.23
MPC		1.5
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.042	Neutral
Varity_R		0.82
gMVP		0.94
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs751925742; hg19: chr8-97274366;