Genetic Variant NM_030943.4:c.1014_1021delCCTCGGCG (chr14-102930171-CCCTCGGCG-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_030943.4(AMN):c.1014_1021delCCTCGGCG(p.Leu339ProfsTer167) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000749 in 1,335,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A338A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

AMN
NM_030943.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.94

Publications

1 publications found

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]

AMN Gene-Disease associations (from GenCC):

Imerslund-Grasbeck syndrome type 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Imerslund-Grasbeck syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AMN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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 14-102930171-CCCTCGGCG-C is Pathogenic according to our data. Variant chr14-102930171-CCCTCGGCG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56744.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMN	NM_030943.4 link	c.1014_1021delCCTCGGCG	p.Leu339ProfsTer167	frameshift_variant	Exon 10 of 12	ENST00000299155.10	NP_112205.2	Q9BXJ7-1
AMN	NM_001425246.1 link	c.852_859delCCTCGGCG	p.Leu285ProfsTer167	frameshift_variant	Exon 10 of 12		NP_001412175.1
AMN	XM_011537203.4 link	c.852_859delCCTCGGCG	p.Leu285ProfsTer167	frameshift_variant	Exon 10 of 12		XP_011535505.1	B3KP64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMN	ENST00000299155.10 link	c.1014_1021delCCTCGGCG	p.Leu339ProfsTer167	frameshift_variant	Exon 10 of 12	1	NM_030943.4	ENSP00000299155.6		Q9BXJ7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

95280

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

7.49e-7

AC:

AN:

1335512

Hom.:

AF XY:

0.00

AC XY:

AN XY:

659262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26748

American (AMR)

AF:

0.0000339

AC:

AN:

29536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23204

East Asian (EAS)

AF:

0.00

AC:

AN:

30688

South Asian (SAS)

AF:

0.00

AC:

AN:

74300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3898

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057786

Other (OTH)

AF:

0.00

AC:

AN:

55192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome

Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=11/189

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over