chr14-102930400-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_030943.4(AMN):c.1170-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,515,198 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 6 hom., cov: 34)

Exomes 𝑓: 0.0017 ( 11 hom. )

Consequence

AMN
NM_030943.4 splice_region, intron

Scores

Splicing: ADA: 0.00006617

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: -0.368

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 14-102930400-C-T is Benign according to our data. Variant chr14-102930400-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56745.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00287 (437/152236) while in subpopulation NFE AF = 0.00194 (132/67970). AF 95% confidence interval is 0.00167. There are 6 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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.1170-6C>T		splice_region intron	N/A	NP_112205.2	Q9BXJ7-1
	AMN	NM_001425246.1		c.1008-6C>T		splice_region intron	N/A	NP_001412175.1	B3KP64

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AMN	ENST00000299155.10	TSL:1 MANE Select	c.1170-6C>T	splice_region intron	N/A	ENSP00000299155.6	Q9BXJ7-1
AMN	ENST00000872999.1		c.1113-6C>T	splice_region intron	N/A	ENSP00000543058.1
AMN	ENST00000559789.1	TSL:3	c.288-6C>T	splice_region intron	N/A	ENSP00000452831.1	H0YKJ5

Frequencies

GnomAD3 genomes

AF:

0.00288

AC:

438

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00212

AC:

241

AN:

113898

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.000285

Gnomad AMR exome

AF:

0.000613

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0254

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00140

GnomAD4 exome

AF:

0.00165

AC:

2254

AN:

1362962

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1070

AN XY:

671594

show subpopulations

African (AFR)

AF:

0.000275

AC:

AN:

29046

American (AMR)

AF:

0.000645

AC:

AN:

34098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24322

East Asian (EAS)

AF:

0.00

AC:

AN:

33776

South Asian (SAS)

AF:

0.000597

AC:

AN:

77048

European-Finnish (FIN)

AF:

0.0188

AC:

633

AN:

33672

Middle Eastern (MID)

AF:

0.00171

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00136

AC:

1454

AN:

1070134

Other (OTH)

AF:

0.00148

AC:

AN:

56776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

136

272

409

545

681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00287

AC:

437

AN:

152236

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

284

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41566

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0253

AC:

268

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00194

AC:

132

AN:

67970

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00194

Hom.:

Bravo

AF:

0.00102

Asia WGS

AF:

0.000579

AC:

AN:

3466

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Imerslund-Grasbeck syndrome (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.7

(source)

DANN

Benign

0.92

PhyloP100

-0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over