Genetic Variant PLAC1:p.Ala70Thr (chrX-134566475-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021796.4(PLAC1):c.208G>A(p.Ala70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,097,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 5 hem. )

Consequence

PLAC1
NM_021796.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.50

Variant links:

Genes affected

PLAC1 (HGNC:9044): (placenta enriched 1) Involved in placenta development. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PLAC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.081887275).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAC1	NM_021796.4 link	c.208G>A	p.Ala70Thr	missense_variant	Exon 3 of 3	ENST00000359237.9	NP_068568.1	Q9HBJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLAC1	ENST00000359237.9 link	c.208G>A	p.Ala70Thr	missense_variant	Exon 3 of 3	1	NM_021796.4	ENSP00000352173.4	Q9HBJ0
PLAC1	ENST00000476971.5 link	n.540G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5
PLAC1	ENST00000473897.1 link	n.*35G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000382

AC:

AN:

183336

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67810

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:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097697

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363053

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:

0.000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208G>A (p.A70T) alteration is located in exon 3 (coding exon 1) of the PLAC1 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the alanine (A) at amino acid position 70 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.4

DANN

Benign

0.74

DEOGEN2

Benign

0.042

FATHMM_MKL

Benign

0.0052

LIST_S2

Benign

0.52

M_CAP

Benign

0.031

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.0

REVEL

Benign

0.25

Sift

Benign

0.43

Sift4G

Benign

0.32

Polyphen

0.88

Vest4

0.047

MutPred

0.19

Gain of relative solvent accessibility (P = 0.09);

MVP

0.70

MPC

0.13

ClinPred

0.047

GERP RS

-7.4

Varity_R

0.062

gMVP

0.41

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

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