14-102928862-C-T

Variant names:

• chr14-102928862-C-T
• rs758317090
• NM_030943.4:c.400C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030943.4(AMN):​c.400C>T​(p.Arg134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AMN NM_030943.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.400C>T	p.Arg134Cys	missense	Exon 5 of 12	NP_112205.2	Q9BXJ7-1
	AMN	NM_001425246.1		c.238C>T	p.Arg80Cys	missense	Exon 5 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.400C>T	p.Arg134Cys	missense	Exon 5 of 12	ENSP00000299155.6	Q9BXJ7-1
	AMN	ENST00000872999.1		c.343C>T	p.Arg115Cys	missense	Exon 5 of 12	ENSP00000543058.1
	AMN	ENST00000559789.1	TSL:3	c.31C>T	p.Arg11Cys	missense	Exon 1 of 4	ENSP00000452831.1	H0YKJ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000832 AC: 2 AN: 240384 AF XY: 0.0000152

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: 0.00000482 AC: 7 AN: 1452202 Hom.: 0 Cov.: 34 AF XY: 0.00000968 AC XY: 7 AN XY: 722842

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111766

Other (OTH) AF: 0.0000166 AC: 1 AN: 60276

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	0.0029	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.013
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.069	T
Polyphen		0.40	B
Vest4		0.38
MutPred		0.56		Gain of catalytic residue at P136 (P = 8e-04)
MVP		0.93
MPC		0.83
ClinPred		0.81	D
GERP RS		4.0
PromoterAI		0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.69
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs758317090; hg19: chr14-103395199;