8-96273333-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_014754.3(PTDSS1):c.214G>A(p.Gly72Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,612,336 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: PTDSS1 NM_014754.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.65

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35919198).
• BP6: Variant 8-96273333-G-A is Benign according to our data. Variant chr8-96273333-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 730485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 156 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTDSS1	NM_014754.3	c.214G>A	p.Gly72Ser	missense_variant	2/13	ENST00000517309.6
LOC105375652	XR_928431.3	n.91-6996C>T		intron_variant, non_coding_transcript_variant
PTDSS1	NM_001290225.2	c.-55G>A		5_prime_UTR_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTDSS1	ENST00000517309.6	c.214G>A	p.Gly72Ser	missense_variant	2/13	1	NM_014754.3	P1
PTDSS1	ENST00000337004.8	c.214G>A	p.Gly72Ser	missense_variant, NMD_transcript_variant	2/11	1
PTDSS1	ENST00000517557.5	n.288G>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000822 AC: 205 AN: 249458 Hom.: 0 AF XY: 0.000815 AC XY: 110 AN XY: 134890

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.000743

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.00129 AC: 1885 AN: 1460054 Hom.: 3 Cov.: 30 AF XY: 0.00122 AC XY: 885 AN XY: 726338

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00158 Hom.: 0

Bravo AF: 0.000782

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.00104

EpiControl AF: 0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.00030	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.83
MVP		0.84
MPC		1.5
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.66
gMVP		0.96

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: rs149279242; hg19: chr8-97285561;