rs386834177

Positions:

• chr14-102929518-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000299155.10(AMN):​c.742C>T​(p.Gln248Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.2e-7 (0 hom.)
• Consequence: AMN ENST00000299155.10 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 1.01

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-102929518-C-T is Pathogenic according to our data. Variant chr14-102929518-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 56759.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-102929518-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMN	NM_030943.4	c.742C>T	p.Gln248Ter	stop_gained	7/12	ENST00000299155.10	NP_112205.2
AMN	XM_011537202.4	c.580C>T	p.Gln194Ter	stop_gained	7/12		XP_011535504.1
AMN	XM_011537203.4	c.580C>T	p.Gln194Ter	stop_gained	7/12		XP_011535505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMN	ENST00000299155.10	c.742C>T	p.Gln248Ter	stop_gained	7/12	1	NM_030943.4	ENSP00000299155	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383810 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 682804

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: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:2 Other:1

not provided, no classification provided	not provided	Inserm U 954, Faculté de Médecine de Nancy	-	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56759). This premature translational stop signal has been observed in individual(s) with clinical features of Imerslund-GraÃàsbeck Syndrome (PMID: 21750092). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln248*) 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). -

Imerslund-Grasbeck syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Jan 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.39	N
MutationTaster	Benign	1.0	A
Vest4		0.83
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs386834177; hg19: chr14-103395855;