14-93721466-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.440A>G(p.Asp147Gly) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D147E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRIMA1 NM_178013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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=0.38611048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIMA1	NM_178013.4	c.440A>G	p.Asp147Gly	missense_variant	5/5	ENST00000393140.6
PRIMA1	XM_011536456.3	c.440A>G	p.Asp147Gly	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIMA1	ENST00000393140.6	c.440A>G	p.Asp147Gly	missense_variant	5/5	1	NM_178013.4	P1
PRIMA1	ENST00000393143.5	c.440A>G	p.Asp147Gly	missense_variant	4/4	1		P1
PRIMA1	ENST00000316227.3	c.*236A>G		3_prime_UTR_variant	5/5	1
PRIMA1	ENST00000477603.5	c.*236A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.440A>G (p.D147G) alteration is located in exon 5 (coding exon 4) of the PRIMA1 gene. This alteration results from a A to G substitution at nucleotide position 440, causing the aspartic acid (D) at amino acid position 147 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.33	T;T
Polyphen		1.0	D;D
Vest4		0.28
MutPred		0.25		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.099
MPC		1.1
ClinPred		0.78	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.70

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: rs2076037415; hg19: chr14-94187812;