rs139674492

Positions:

• chr14-93721504-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_178013.4(PRIMA1):​c.402G>A​(p.Glu134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PRIMA1 NM_178013.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.880

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 Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-93721504-C-T is Benign according to our data. Variant chr14-93721504-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 476373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.88 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIMA1	NM_178013.4	c.402G>A	p.Glu134=	synonymous_variant	5/5	ENST00000393140.6
PRIMA1	XM_011536456.3	c.402G>A	p.Glu134=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIMA1	ENST00000393140.6	c.402G>A	p.Glu134=	synonymous_variant	5/5	1	NM_178013.4	P1
PRIMA1	ENST00000393143.5	c.402G>A	p.Glu134=	synonymous_variant	4/4	1		P1
PRIMA1	ENST00000316227.3	c.*198G>A		3_prime_UTR_variant	5/5	1
PRIMA1	ENST00000477603.5	c.*198G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251286 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135822

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.0000976 AC XY: 71 AN XY: 727158

Gnomad4 AFR exome AF: 0.00347

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74420

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000661 Hom.: 0

Bravo AF: 0.00127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sleep-related hypermotor epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

PRIMA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.7
DANN	Benign	0.53

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: rs139674492; hg19: chr14-94187850;