14-93721455-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178013.4(PRIMA1):c.451G>A(p.Ala151Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. A151P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PRIMA1 NM_178013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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]

ACMG classification

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=0.034697413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIMA1	NM_178013.4	c.451G>A	p.Ala151Thr	missense_variant	5/5	ENST00000393140.6
PRIMA1	XM_011536456.3	c.451G>A	p.Ala151Thr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIMA1	ENST00000393140.6	c.451G>A	p.Ala151Thr	missense_variant	5/5	1	NM_178013.4	P1
PRIMA1	ENST00000393143.5	c.451G>A	p.Ala151Thr	missense_variant	4/4	1		P1
PRIMA1	ENST00000316227.3	c.*247G>A		3_prime_UTR_variant	5/5	1
PRIMA1	ENST00000477603.5	c.*247G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 250972 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1458940 Hom.: 0 Cov.: 28 AF XY: 0.0000427 AC XY: 31 AN XY: 726008

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: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sleep-related hypermotor epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 151 of the PRIMA1 protein (p.Ala151Thr). This variant is present in population databases (rs200782279, gnomAD 0.05%). 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: 1026361). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.064
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.051
Sift	Benign	0.27	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.17	B;B
Vest4		0.14
MVP		0.040
MPC		0.37
ClinPred		0.041	T
GERP RS		3.9
Varity_R		0.050
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200782279; hg19: chr14-94187801; COSMIC: COSV60263331;