14-102930629-CCA-C

Position:

• chr14-102930629-CCA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_030943.4(AMN):​c.1314_1315del​(p.His438GlnfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,601,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. H438H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: AMN NM_030943.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.555

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0367 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-102930629-CCA-C is Pathogenic according to our data. Variant chr14-102930629-CCA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56748.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-102930629-CCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMN	NM_030943.4	c.1314_1315del	p.His438GlnfsTer?	frameshift_variant	12/12	ENST00000299155.10
AMN	XM_011537202.4	c.1152_1153del	p.His384GlnfsTer?	frameshift_variant	12/12
AMN	XM_011537203.4	c.1152_1153del	p.His384GlnfsTer?	frameshift_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMN	ENST00000299155.10	c.1314_1315del	p.His438GlnfsTer?	frameshift_variant	12/12	1	NM_030943.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000905 AC: 2 AN: 220924 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121014

Gnomad AFR exome AF: 0.0000767

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.0000104 AC: 15 AN: 1449160 Hom.: 0 AF XY: 0.00000695 AC XY: 5 AN XY: 719898

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2023	This sequence change results in a frameshift in the AMN gene (p.His438Glnfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the AMN protein and extend the protein by an uncertain number of additional amino acid residues. This variant is present in population databases (rs767203418, gnomAD 0.008%). This frameshift has been observed in individual(s) with Imerslund-GraÃàsbeck syndrome (PMID: 22929189). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56748). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs386834167; hg19: chr14-103396966;