14-93721523-T-C

Position:

• chr14-93721523-T-C

Variant summary

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

The NM_178013.4(PRIMA1):​c.383A>G​(p.Asn128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRIMA1 NM_178013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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=0.30983567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRIMA1	NM_178013.4	c.383A>G	p.Asn128Ser	missense_variant	5/5	ENST00000393140.6	NP_821092.1
PRIMA1	XM_011536456.3	c.383A>G	p.Asn128Ser	missense_variant	5/5		XP_011534758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRIMA1	ENST00000393140.6	c.383A>G	p.Asn128Ser	missense_variant	5/5	1	NM_178013.4	ENSP00000376848	P1
PRIMA1	ENST00000393143.5	c.383A>G	p.Asn128Ser	missense_variant	4/4	1		ENSP00000376851	P1
PRIMA1	ENST00000316227.3	c.*179A>G		3_prime_UTR_variant	5/5	1		ENSP00000320948
PRIMA1	ENST00000477603.5	c.*179A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	1		ENSP00000434370

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 29, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 128 of the PRIMA1 protein (p.Asn128Ser). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.077	T;T
Polyphen		0.97	D;D
Vest4		0.19
MutPred		0.14		Gain of glycosylation at N128 (P = 0.0222);Gain of glycosylation at N128 (P = 0.0222);
MVP		0.076
MPC		0.70
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2076038151; hg19: chr14-94187869;