rs12883949

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_030943.4(AMN):​c.761-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

AMN
NM_030943.4 splice_acceptor, intron

Scores

1
2
4
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.99
Variant links:
Genes affected
AMN (HGNC:14604): (amnion associated transmembrane protein) The protein encoded by this gene is a type I transmembrane protein. It is thought to modulate bone morphogenetic protein (BMP) receptor function by serving as an accessory or coreceptor, and thus facilitates or hinders BMP binding. It is known that the mouse AMN gene is expressed in the extraembryonic visceral endoderm layer during gastrulation, but it is found to be mutated in amnionless mouse. The encoded protein has sequence similarity to short gastrulation (Sog) and procollagen IIA proteins in Drosophila. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AMNNM_030943.4 linkuse as main transcriptc.761-1G>A splice_acceptor_variant, intron_variant ENST00000299155.10 NP_112205.2 Q9BXJ7-1
AMNXM_011537202.4 linkuse as main transcriptc.599-1G>A splice_acceptor_variant, intron_variant B3KP64
AMNXM_011537203.4 linkuse as main transcriptc.599-1G>A splice_acceptor_variant, intron_variant XP_011535505.1 B3KP64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AMNENST00000299155.10 linkuse as main transcriptc.761-1G>A splice_acceptor_variant, intron_variant 1 NM_030943.4 ENSP00000299155.6 Q9BXJ7-1
AMNENST00000559789.1 linkuse as main transcriptc.125-511G>A intron_variant 3 ENSP00000452831.1 H0YKJ5
AMNENST00000541086.5 linkuse as main transcriptn.1507-1G>A splice_acceptor_variant, intron_variant 2
AMNENST00000558590.1 linkuse as main transcriptn.724-1G>A splice_acceptor_variant, intron_variant 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1397010
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
689084
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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.:
33
Alfa
AF:
0.0000585
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
28
DANN
Benign
0.97
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Benign
0.61
D
GERP RS
3.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.75
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.50
Position offset: 2
DS_AL_spliceai
0.99
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.

Other links and lift over

dbSNP: rs12883949; hg19: chr14-103395991; API