rs146499374

chr14-102929723-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:4
• Conservation: PhyloP100: -1.92

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMN	NM_030943.4	c.829A>G	p.Thr277Ala	missense_variant	8/12	ENST00000299155.10
AMN	XM_011537202.4	c.667A>G	p.Thr223Ala	missense_variant	8/12
AMN	XM_011537203.4	c.667A>G	p.Thr223Ala	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMN	ENST00000299155.10	c.829A>G	p.Thr277Ala	missense_variant	8/12	1	NM_030943.4	P1
AMN	ENST00000559789.1	c.127-442A>G		intron_variant		3
AMN	ENST00000541086.5	n.1575A>G		non_coding_transcript_exon_variant	7/11	2
AMN	ENST00000558590.1	n.792A>G		non_coding_transcript_exon_variant	3/9	2

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

GnomAD3 exomes AF: 0.00496 AC: 766 AN: 154394 Hom.: 3 AF XY: 0.00527 AC XY: 434 AN XY: 82330

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 SAS exome AF: 0.0105

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

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.000596

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.00897

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00713

Gnomad4 OTH exome AF: 0.00608

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

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00696

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00600 Hom.: 3

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AMN: BS1, BS2 -

Imerslund-Grasbeck syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

- -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs146499374; hg19: chr14-103396060;