dbSNP rs1221627092: PRIMA1:p.Arg55Gln (chr14-93779241-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_178013.4(PRIMA1):c.164G>A(p.Arg55Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000022 in 1,364,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

PRIMA1
NM_178013.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.56

Publications

1 publications found

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 was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRIMA1	NM_178013.4 link	c.164G>A	p.Arg55Gln	missense_variant	Exon 3 of 5	ENST00000393140.6	NP_821092.1	Q86XR5-1A0A024R6J9
PRIMA1	XM_011536456.3 link	c.164G>A	p.Arg55Gln	missense_variant	Exon 3 of 5		XP_011534758.1	Q86XR5-1A0A024R6J9
PRIMA1	XM_047430966.1 link	c.164G>A	p.Arg55Gln	missense_variant	Exon 3 of 5		XP_047286922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRIMA1	ENST00000393140.6 link	c.164G>A	p.Arg55Gln	missense_variant	Exon 3 of 5	1	NM_178013.4	ENSP00000376848.1	Q86XR5-1
PRIMA1	ENST00000393143.5 link	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 4	1		ENSP00000376851.1	Q86XR5-1
PRIMA1	ENST00000316227.3 link	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 5	1		ENSP00000320948.3	Q86XR5-2
PRIMA1	ENST00000477603.5 link	n.164G>A		non_coding_transcript_exon_variant	Exon 3 of 6	1		ENSP00000434370.1	Q86XR5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000220

AC:

AN:

1364444

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

677152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27660

American (AMR)

AF:

0.00

AC:

AN:

27626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23466

East Asian (EAS)

AF:

0.00

AC:

AN:

34076

South Asian (SAS)

AF:

0.0000140

AC:

AN:

71232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4560

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1070456

Other (OTH)

AF:

0.00

AC:

AN:

56588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial sleep-related hypermotor epilepsy

Uncertain:1

Aug 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 542927). This variant has not been reported in the literature in individuals affected with PRIMA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 55 of the PRIMA1 protein (p.Arg55Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0054

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

4.6

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Benign

0.21

Sift

Benign

0.075

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.66

MutPred

0.096

Gain of helix (P = 0.2684);Gain of helix (P = 0.2684);Gain of helix (P = 0.2684);

MVP

0.21

MPC

0.34

ClinPred

0.98

GERP RS

4.9

Varity_R

0.41

gMVP

0.88

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over