4-70522834-A-G

Variant names:

• chr4-70522834-A-G
• rs7660807
• NM_212557.4:c.134A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_212557.4(AMTN):​c.134A>G​(p.Asn45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,613,322 control chromosomes in the GnomAD database, including 7,933 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.078 (681 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7252 hom.)
• Consequence: AMTN NM_212557.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.248
• Publications: 18 publications found

Genes affected

AMTN (HGNC:33188): (amelotin) The mineralized portions of teeth, the dentin and enamel, are formed by mesenchyme-derived odontoblasts and epithelium-derived ameloblasts, respectively. As ameloblasts differentiate, they deposit specific proteins necessary for enamel formation, including amelogenin (AMELX; MIM 300391), enamelin (ENAM; MIM 606585), and ameloblastin (AMBN; MIM 601259), in the organic enamel matrix. Amelotin is specifically expressed in maturation-stage ameloblasts (Iwasaki et al., 2005 [PubMed 16304441]).[supplied by OMIM, Mar 2008]

AMTN Gene-Disease associations (from GenCC):

• amelogenesis imperfecta, type 3A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amelogenesis imperfecta type 3B

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015470088).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMTN	NM_212557.4	c.134A>G	p.Asn45Ser	missense_variant	Exon 3 of 9	ENST00000339336.9	NP_997722.1
AMTN	NM_001286731.2	c.131A>G	p.Asn44Ser	missense_variant	Exon 3 of 9		NP_001273660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMTN	ENST00000339336.9	c.134A>G	p.Asn45Ser	missense_variant	Exon 3 of 9	1	NM_212557.4	ENSP00000341013.4
AMTN	ENST00000504451.1	c.131A>G	p.Asn44Ser	missense_variant	Exon 3 of 9	1		ENSP00000422452.1

Frequencies

GnomAD3 genomes AF: 0.0780 AC: 11864 AN: 152096 Hom.: 681 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0846

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.105 AC: 26312 AN: 250858 AF XY: 0.111

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.0404

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.0951

GnomAD4 exome AF: 0.0921 AC: 134575 AN: 1461108 Hom.: 7252 Cov.: 31 AF XY: 0.0944 AC XY: 68608 AN XY: 726858

African (AFR) AF: 0.0140 AC: 470 AN: 33478

American (AMR) AF: 0.0419 AC: 1876 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2894 AN: 26116

East Asian (EAS) AF: 0.190 AC: 7538 AN: 39680

South Asian (SAS) AF: 0.170 AC: 14689 AN: 86238

European-Finnish (FIN) AF: 0.176 AC: 9418 AN: 53388

Middle Eastern (MID) AF: 0.117 AC: 673 AN: 5758

European-Non Finnish (NFE) AF: 0.0822 AC: 91361 AN: 1111380

Other (OTH) AF: 0.0937 AC: 5656 AN: 60350

GnomAD4 genome AF: 0.0779 AC: 11865 AN: 152214 Hom.: 681 Cov.: 32 AF XY: 0.0847 AC XY: 6306 AN XY: 74408

African (AFR) AF: 0.0167 AC: 695 AN: 41552

American (AMR) AF: 0.0620 AC: 947 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3472

East Asian (EAS) AF: 0.193 AC: 1001 AN: 5174

South Asian (SAS) AF: 0.172 AC: 828 AN: 4826

European-Finnish (FIN) AF: 0.178 AC: 1885 AN: 10588

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0846 AC: 5751 AN: 68006

Other (OTH) AF: 0.0691 AC: 146 AN: 2114

Alfa AF: 0.0821 Hom.: 2089

Bravo AF: 0.0648

TwinsUK AF: 0.0852 AC: 316

ALSPAC AF: 0.0797 AC: 307

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.0821 AC: 706

ExAC AF: 0.106 AC: 12860

Asia WGS AF: 0.167 AC: 580 AN: 3476

EpiCase AF: 0.0876

EpiControl AF: 0.0893

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.0
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		-0.25
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.10
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.043	D;D
Polyphen		0.10	B;B
Vest4		0.040
MPC		0.058
ClinPred		0.0059	T
GERP RS		1.4
Varity_R		0.063
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7660807; hg19: chr4-71388551; COSMIC: COSV59488824;