chr14-102930052-G-GGCCC

Variant names:

• chr14-102930052-G-GGCCC
• rs386834179
• NM_030943.4:c.974_977dupCCCG

Variant summary

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

The NM_030943.4(AMN):​c.974_977dupCCCG​(p.Ala327ProfsTer183) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AMN NM_030943.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.54
• 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 14-102930052-G-GGCCC is Pathogenic according to our data. Variant chr14-102930052-G-GGCCC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56761.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.974_977dupCCCG	p.Ala327ProfsTer183	frameshift	Exon 9 of 12	NP_112205.2	Q9BXJ7-1
	AMN	NM_001425246.1		c.812_815dupCCCG	p.Ala273ProfsTer183	frameshift	Exon 9 of 12	NP_001412175.1	B3KP64

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMN	ENST00000299155.10	TSL:1 MANE Select	c.974_977dupCCCG	p.Ala327ProfsTer183	frameshift	Exon 9 of 12	ENSP00000299155.6	Q9BXJ7-1
	AMN	ENST00000872999.1		c.917_920dupCCCG	p.Ala308ProfsTer183	frameshift	Exon 9 of 12	ENSP00000543058.1
	AMN	ENST00000559789.1	TSL:3	c.125-111_125-108dupCCCG		intron	N/A	ENSP00000452831.1	H0YKJ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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		2.5
Mutation Taster		=20/180	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386834179; hg19: chr14-103396389;