rs1449284468

Positions:

• chr14-93787628-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178013.4(PRIMA1):​c.91C>G​(p.Gln31Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000144 in 1,388,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRIMA1 NM_178013.4 missense, splice_region
• Scores: Splicing: ADA: 0.8155
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30734682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIMA1	NM_178013.4	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant	2/5	ENST00000393140.6
PRIMA1	XM_011536456.3	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant	2/5
PRIMA1	XM_047430966.1	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIMA1	ENST00000393140.6	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant	2/5	1	NM_178013.4	P1
PRIMA1	ENST00000393143.5	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant	1/4	1		P1
PRIMA1	ENST00000316227.3	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant	1/5	1
PRIMA1	ENST00000477603.5	c.91C>G	p.Gln31Glu	missense_variant, splice_region_variant, NMD_transcript_variant	2/6	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388966 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 685550

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces glutamine with glutamic acid at codon 31 of the PRIMA1 protein (p.Gln31Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. 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: 476374). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.042	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.81	P;P;.
Vest4		0.41
MutPred		0.37		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.28
MPC		0.86
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.34
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1449284468; hg19: chr14-94253974;