14-93721473-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178013.4(PRIMA1):c.433G>A(p.Gly145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PRIMA1
NM_178013.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50

Variant links:

Genes affected

PRIMA1 (HGNC:18319): (proline rich membrane anchor 1) The product of this gene functions to organize acetylcholinesterase (AChE) into tetramers, and to anchor AChE at neural cell membranes. [provided by RefSeq, Nov 2008]

PRIMA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10093573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIMA1	NM_178013.4 linkuse as main transcript	c.433G>A	p.Gly145Arg	missense_variant	5/5	ENST00000393140.6
PRIMA1	XM_011536456.3 linkuse as main transcript	c.433G>A	p.Gly145Arg	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIMA1	ENST00000393140.6 linkuse as main transcript	c.433G>A	p.Gly145Arg	missense_variant	5/5	1	NM_178013.4	P1	Q86XR5-1
PRIMA1	ENST00000393143.5 linkuse as main transcript	c.433G>A	p.Gly145Arg	missense_variant	4/4	1		P1	Q86XR5-1
PRIMA1	ENST00000316227.3 linkuse as main transcript	c.*229G>A		3_prime_UTR_variant	5/5	1			Q86XR5-2
PRIMA1	ENST00000477603.5 linkuse as main transcript	c.*229G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	1			Q86XR5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251256

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Sleep-related hypermotor epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

This sequence change replaces glycine with arginine at codon 145 of the PRIMA1 protein (p.Gly145Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs779293897, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with PRIMA1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.36

M_CAP

Benign

0.013

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.075

Sift

Benign

0.097

T;T

Sift4G

Benign

0.067

T;T

Polyphen

0.90

P;P

Vest4

0.21

MutPred

0.28

Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);

MVP

0.13

MPC

0.75

ClinPred

0.17

GERP RS

3.6

Varity_R

0.083

gMVP

0.82

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