rs386834163

Variant names:

• chr14-102930171-CCCTCGGCG-C
• rs386834163
• NM_030943.4:c.1014_1021delCCTCGGCG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

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
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.94
• Publications: 1 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030943.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMN	NM_030943.4	MANE Select	c.1014_1021delCCTCGGCG	p.Leu339ProfsTer167	frameshift	Exon 10 of 12	NP_112205.2
	AMN	NM_001425246.1		c.852_859delCCTCGGCG	p.Leu285ProfsTer167	frameshift	Exon 10 of 12	NP_001412175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMN	ENST00000299155.10	TSL:1 MANE Select	c.1014_1021delCCTCGGCG	p.Leu339ProfsTer167	frameshift	Exon 10 of 12	ENSP00000299155.6
	AMN	ENST00000872999.1		c.957_964delCCTCGGCG	p.Leu320ProfsTer167	frameshift	Exon 10 of 12	ENSP00000543058.1
	AMN	ENST00000559789.1	TSL:3	c.132_139delCCTCGGCG	p.Leu45LeufsTer84	frameshift	Exon 2 of 4	ENSP00000452831.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 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: 1 AN: 1335512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 659262

African (AFR) AF: 0.00 AC: 0 AN: 26748

American (AMR) AF: 0.0000339 AC: 1 AN: 29536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23204

East Asian (EAS) AF: 0.00 AC: 0 AN: 30688

South Asian (SAS) AF: 0.00 AC: 0 AN: 74300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057786

Other (OTH) AF: 0.00 AC: 0 AN: 55192

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386834163; hg19: chr14-103396508;