Variant 12-31697841-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000281471.11(AMN1):c.433A>G(p.Ile145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

AMN1
ENST00000281471.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0960

Variant links:

Genes affected

AMN1 (HGNC:27281): (antagonist of mitotic exit network 1 homolog) Predicted to be involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

AMN1 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
AMN1	NM_001113402.2 linkuse as main transcript	c.433A>G	p.Ile145Val	missense_variant	4/7	ENST00000281471.11	NP_001106873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMN1	ENST00000281471.11 linkuse as main transcript	c.433A>G	p.Ile145Val	missense_variant	4/7	1	NM_001113402.2	ENSP00000281471	P1	Q8IY45-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248920

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

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.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.433A>G (p.I145V) alteration is located in exon 4 (coding exon 4) of the AMN1 gene. This alteration results from a A to G substitution at nucleotide position 433, causing the isoleucine (I) at amino acid position 145 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.026

T;.;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.70

T;.;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.047

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.23

N;.;.;.

MutationTaster

Benign

0.77

D;D;D;D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

0.17

N;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.87

T;T;T;T

Sift4G

Benign

0.80

T;T;T;.

Polyphen

0.0

B;.;.;.

Vest4

0.10

MutPred

0.45

Gain of catalytic residue at G150 (P = 8e-04);.;.;.;

MVP

0.22

MPC

0.37

ClinPred

0.030

GERP RS

0.26

Varity_R

0.015

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over