rs386834174

chr14-102929439-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_030943.4(AMN):c.663G>A(p.Trp221Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AMN NM_030943.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-102929439-G-A is Pathogenic according to our data. Variant chr14-102929439-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 56756.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-102929439-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMN	NM_030943.4	c.663G>A	p.Trp221Ter	stop_gained	7/12	ENST00000299155.10
AMN	XM_011537202.4	c.501G>A	p.Trp167Ter	stop_gained	7/12
AMN	XM_011537203.4	c.501G>A	p.Trp167Ter	stop_gained	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMN	ENST00000299155.10	c.663G>A	p.Trp221Ter	stop_gained	7/12	1	NM_030943.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1378776 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 680298

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 02, 2023	This sequence change creates a premature translational stop signal (p.Trp221*) in the AMN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AMN are known to be pathogenic (PMID: 12590260, 22929189). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with AMN-related conditions (PMID: 22631584, 22929189). ClinVar contains an entry for this variant (Variation ID: 56756). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	37
Dann	Uncertain	0.98
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.41	N
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs386834174; hg19: chr14-103395776;