Genetic Variant PLAC1:p.Arg76His (chrX-134566456-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.227G>A(p.Arg76His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,210,318 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000054 ( 0 hom. 23 hem. )

Consequence

PLAC1
NM_021796.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

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=0.0771589).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLAC1	NM_021796.4 link	c.227G>A	p.Arg76His	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.227G>A	p.Arg76His	missense_variant	Exon 3 of 3	1	NM_021796.4	ENSP00000352173.4	Q9HBJ0
PLAC1	ENST00000476971.5 link	n.559G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5
PLAC1	ENST00000473897.1 link	n.*54G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112176

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

34352

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000558

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000191

AC:

AN:

183339

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

67823

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00209

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000537

AC:

AN:

1098088

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363442

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00119

Gnomad4 SAS exome

AF:

0.000148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112230

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34416

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000559

Gnomad4 SAS

AF:

0.000372

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.227G>A (p.R76H) 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 227, causing the arginine (R) at amino acid position 76 to be replaced by a histidine (H). 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

0.22

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.057

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.077

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.58

Sift

Benign

0.26

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.36

MVP

0.73

MPC

0.53

ClinPred

0.096

GERP RS

3.6

Varity_R

0.13

gMVP

0.46

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