14-93787703-A-C

Position:

chr14-93787703-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000393140.6(PRIMA1):c.16T>G(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,544,330 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

PRIMA1
ENST00000393140.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.57

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05372569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRIMA1	NM_178013.4 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant	2/5	ENST00000393140.6	NP_821092.1
PRIMA1	XM_011536456.3 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant	2/5		XP_011534758.1
PRIMA1	XM_047430966.1 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant	2/5		XP_047286922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRIMA1	ENST00000393140.6 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant	2/5	1	NM_178013.4	ENSP00000376848	P1	Q86XR5-1
PRIMA1	ENST00000393143.5 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant	1/4	1		ENSP00000376851	P1	Q86XR5-1
PRIMA1	ENST00000316227.3 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant	1/5	1		ENSP00000320948		Q86XR5-2
PRIMA1	ENST00000477603.5 linkuse as main transcript	c.16T>G	p.Leu6Val	missense_variant, NMD_transcript_variant	2/6	1		ENSP00000434370		Q86XR5-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000149

AC:

AN:

140992

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

75696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000965

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000391

AC:

544

AN:

1391984

Hom.:

Cov.:

AF XY:

0.000387

AC XY:

266

AN XY:

686828

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000469

Gnomad4 NFE exome

AF:

0.000485

Gnomad4 OTH exome

AF:

0.000242

GnomAD4 genome

AF:

0.000276

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000276

Hom.:

Bravo

AF:

0.000249

ExAC

AF:

0.000106

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sleep-related hypermotor epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the PRIMA1 protein (p.Leu6Val). This variant is present in population databases (rs186707302, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PRIMA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542928). 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: "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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

May 12, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.05% (38/68038) (https://gnomad.broadinstitute.org/variant/14-93787703-A-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:542928). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.49

M_CAP

Benign

0.0055

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.059

Sift

Benign

0.083

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.21

B;B;.

Vest4

0.32

MVP

0.085

MPC

0.71

ClinPred

0.086

GERP RS

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.13

gMVP

0.45

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