rs386834161

chr14-102930107-CCGCCCCGCCGCGCCT-Cchr14-102930107-CCGCCCCGCCGCGCCT-CCGCCCCGCCGCGCCTCGCCCCGCCGCGCCTCGCCCCGCCGCGCCTCGCCCCGCCGCGCCT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_030943.4(AMN):c.1006+34_1007-31del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,512,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: AMN NM_030943.4 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.688

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-102930107-CCGCCCCGCCGCGCCT-C is Pathogenic according to our data. Variant chr14-102930107-CCGCCCCGCCGCGCCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 56742.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-102930107-CCGCCCCGCCGCGCCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMN	NM_030943.4	c.1006+34_1007-31del		intron_variant		ENST00000299155.10
AMN	XM_011537202.4	c.844+34_845-31del		intron_variant
AMN	XM_011537203.4	c.844+34_845-31del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMN	ENST00000299155.10	c.1006+34_1007-31del		intron_variant		1	NM_030943.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151992 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000560 AC: 6 AN: 107218 Hom.: 0 AF XY: 0.0000337 AC XY: 2 AN XY: 59396

Gnomad AFR exome AF: 0.000343

Gnomad AMR exome AF: 0.000151

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: 0.0000507

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000544 AC: 74 AN: 1360814 Hom.: 0 AF XY: 0.0000462 AC XY: 31 AN XY: 670812

Gnomad4 AFR exome AF: 0.0000352

Gnomad4 AMR exome AF: 0.000128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000241

Gnomad4 NFE exome AF: 0.0000572

Gnomad4 OTH exome AF: 0.000124

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74356

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

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	Jan 21, 2024	This sequence change falls in intron 9 of the AMN gene. It does not directly change the encoded amino acid sequence of the AMN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs386834161, gnomAD 0.02%). This variant has been observed in individuals with Imerslund-Gräsbeck syndrome (PMID: 22929189, 30691194). This variant is also known as c.1006+34_48del15bp. ClinVar contains an entry for this variant (Variation ID: 56742). Studies have shown that this variant results in skipping of exon 9 and introduces a premature termination codon (PMID: 22929189). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386834161; hg19: chr14-103396444;