chr12-31697949-C-A

Position:

• chr12-31697949-C-A

Variant summary

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

The ENST00000281471.11(AMN1):​c.325G>T​(p.Ala109Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: AMN1 ENST00000281471.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22

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]

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=0.27732843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMN1	NM_001113402.2	c.325G>T	p.Ala109Ser	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	c.325G>T	p.Ala109Ser	missense_variant	4/7	1	NM_001113402.2	ENSP00000281471	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Dec 11, 2023

The c.325G>T (p.A109S) alteration is located in exon 4 (coding exon 4) of the AMN1 gene. This alteration results from a G to T substitution at nucleotide position 325, causing the alanine (A) at amino acid position 109 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;.;.;.
Eigen	Benign	0.085
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.80	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.28	T;T;T;T
Sift4G	Uncertain	0.021	D;D;D;.
Polyphen		0.73	P;.;.;.
Vest4		0.40
MutPred		0.39		Gain of catalytic residue at S112 (P = 0.0031);.;.;.;
MVP		0.37
MPC		1.2
ClinPred		0.90	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.32

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: rs1448449496; hg19: chr12-31850883;