14-102929723-A-G

Variant names:

• chr14-102929723-A-G
• rs146499374
• NM_030943.4:c.829A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030943.4(AMN):​c.829A>G​(p.Thr277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,550,414 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T277T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (43 hom.)
• Consequence: AMN NM_030943.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.92
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005910963).
• BP6: Variant 14-102929723-A-G is Benign according to our data. Variant chr14-102929723-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00457 (695/152030) while in subpopulation SAS AF = 0.0122 (59/4818). AF 95% confidence interval is 0.00975. There are 5 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMN	NM_030943.4	MANE Select	c.829A>G	p.Thr277Ala	missense	Exon 8 of 12	NP_112205.2
	AMN	NM_001425246.1		c.667A>G	p.Thr223Ala	missense	Exon 8 of 12	NP_001412175.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMN	ENST00000299155.10	TSL:1 MANE Select	c.829A>G	p.Thr277Ala	missense	Exon 8 of 12	ENSP00000299155.6
	AMN	ENST00000541086.5	TSL:2	n.1575A>G		non_coding_transcript_exon	Exon 7 of 11
	AMN	ENST00000558590.1	TSL:2	n.792A>G		non_coding_transcript_exon	Exon 3 of 9

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 695 AN: 151912 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00696

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00496 AC: 766 AN: 154394 AF XY: 0.00527

Gnomad AFR exome AF: 0.000860

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00712

GnomAD4 exome AF: 0.00648 AC: 9060 AN: 1398384 Hom.: 43 Cov.: 33 AF XY: 0.00661 AC XY: 4558 AN XY: 689842

African (AFR) AF: 0.00101 AC: 32 AN: 31634

American (AMR) AF: 0.00418 AC: 150 AN: 35880

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 15 AN: 25176

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35832

South Asian (SAS) AF: 0.00897 AC: 711 AN: 79244

European-Finnish (FIN) AF: 0.00135 AC: 65 AN: 48158

Middle Eastern (MID) AF: 0.00833 AC: 42 AN: 5040

European-Non Finnish (NFE) AF: 0.00713 AC: 7692 AN: 1079486

Other (OTH) AF: 0.00608 AC: 352 AN: 57934

GnomAD4 genome AF: 0.00457 AC: 695 AN: 152030 Hom.: 5 Cov.: 33 AF XY: 0.00413 AC XY: 307 AN XY: 74322

African (AFR) AF: 0.00140 AC: 58 AN: 41494

American (AMR) AF: 0.00510 AC: 78 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5116

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4818

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10606

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00696 AC: 473 AN: 67914

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00595 Hom.: 4

Bravo AF: 0.00473

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000953 AC: 4

ESP6500EA AF: 0.00533 AC: 44

ExAC AF: 0.00216 AC: 215

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AMN: BS2

Imerslund-Grasbeck syndrome type 2 Benign:1

Sep 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Imerslund-Grasbeck syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.24
DANN	Benign	0.55
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.64	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.51
MPC		0.50
ClinPred		0.0027	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.51
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs146499374; hg19: chr14-103396060; COSMIC: COSV106102758; COSMIC: COSV106102758;