rs386834178

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_030943.4(AMN):c.761G>A(p.Gly254Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000775 in 1,549,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G254G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

AMN
NM_030943.4 missense, splice_region

Scores

Splicing: ADA: 0.6902

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.95

Publications

2 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 14-102929655-G-A is Pathogenic according to our data. Variant chr14-102929655-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56760.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.761G>A	p.Gly254Glu	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000299155.10	NP_112205.2	Q9BXJ7-1
AMN	NM_001425246.1 link	c.599G>A	p.Gly200Glu	missense_variant, splice_region_variant	Exon 8 of 12		NP_001412175.1
AMN	XM_011537203.4 link	c.599G>A	p.Gly200Glu	missense_variant, splice_region_variant	Exon 8 of 12		XP_011535505.1	B3KP64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMN	ENST00000299155.10 link	c.761G>A	p.Gly254Glu	missense_variant, splice_region_variant	Exon 8 of 12	1	NM_030943.4	ENSP00000299155.6		Q9BXJ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000716

AC:

AN:

1397044

Hom.:

Cov.:

AF XY:

0.00000726

AC XY:

AN XY:

689094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31574

American (AMR)

AF:

0.00

AC:

AN:

35734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4776

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1078938

Other (OTH)

AF:

0.00

AC:

AN:

57856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.075

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.94

MutPred

0.57

Gain of helix (P = 0.0128);

MVP

0.93

MPC

1.6

ClinPred

1.0

GERP RS

3.1

Varity_R

0.92

gMVP

0.95

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.69

dbscSNV1_RF

Benign

0.51

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.51

Position offset: 3

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over