rs1221627092

chr14-93779241-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIMA1	NM_178013.4	c.164G>A	p.Arg55Gln	missense_variant	3/5	ENST00000393140.6
PRIMA1	XM_011536456.3	c.164G>A	p.Arg55Gln	missense_variant	3/5
PRIMA1	XM_047430966.1	c.164G>A	p.Arg55Gln	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIMA1	ENST00000393140.6	c.164G>A	p.Arg55Gln	missense_variant	3/5	1	NM_178013.4	P1
PRIMA1	ENST00000393143.5	c.164G>A	p.Arg55Gln	missense_variant	2/4	1		P1
PRIMA1	ENST00000316227.3	c.164G>A	p.Arg55Gln	missense_variant	2/5	1
PRIMA1	ENST00000477603.5	c.164G>A	p.Arg55Gln	missense_variant, NMD_transcript_variant	3/6	1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1364444 Hom.: 0 Cov.: 29 AF XY: 0.00000295 AC XY: 2 AN XY: 677152

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: 0.0000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000187

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Aug 12, 2022

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	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.85	D
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	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.88

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

Other links and lift over

dbSNP: rs1221627092; hg19: chr14-94245587;