chr4-70518820-C-T

Variant names:

• chr4-70518820-C-T
• rs35286445
• NM_212557.4:c.43C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_212557.4(AMTN):​c.43C>T​(p.Arg15Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,604,560 control chromosomes in the GnomAD database, including 14,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.10 (1081 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13453 hom.)
• Consequence: AMTN NM_212557.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.32
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011405349).
• BP6: Variant 4-70518820-C-T is Benign according to our data. Variant chr4-70518820-C-T is described in ClinVar as Benign. ClinVar VariationId is 3058967.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212557.4. 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
	AMTN	NM_212557.4	MANE Select	c.43C>T	p.Arg15Trp	missense	Exon 2 of 9	NP_997722.1	F1T0L8
	AMTN	NM_001286731.2		c.43C>T	p.Arg15Trp	missense	Exon 2 of 9	NP_001273660.1	Q6UX39-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMTN	ENST00000339336.9	TSL:1 MANE Select	c.43C>T	p.Arg15Trp	missense	Exon 2 of 9	ENSP00000341013.4	Q6UX39-1
	AMTN	ENST00000504451.1	TSL:1	c.43C>T	p.Arg15Trp	missense	Exon 2 of 9	ENSP00000422452.1	Q6UX39-2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15834 AN: 152082 Hom.: 1075 Cov.: 32

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0846

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.127 AC: 31960 AN: 250934 AF XY: 0.132

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.0923

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.131 AC: 190276 AN: 1452360 Hom.: 13453 Cov.: 33 AF XY: 0.133 AC XY: 95979 AN XY: 722912

African (AFR) AF: 0.0280 AC: 934 AN: 33406

American (AMR) AF: 0.0956 AC: 4270 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4487 AN: 26042

East Asian (EAS) AF: 0.198 AC: 7833 AN: 39582

South Asian (SAS) AF: 0.139 AC: 11913 AN: 86000

European-Finnish (FIN) AF: 0.0962 AC: 5135 AN: 53374

Middle Eastern (MID) AF: 0.206 AC: 1182 AN: 5742

European-Non Finnish (NFE) AF: 0.133 AC: 146466 AN: 1103444

Other (OTH) AF: 0.134 AC: 8056 AN: 60098

GnomAD4 genome AF: 0.104 AC: 15839 AN: 152200 Hom.: 1081 Cov.: 32 AF XY: 0.103 AC XY: 7698 AN XY: 74404

African (AFR) AF: 0.0323 AC: 1344 AN: 41556

American (AMR) AF: 0.117 AC: 1780 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3468

East Asian (EAS) AF: 0.186 AC: 964 AN: 5180

South Asian (SAS) AF: 0.142 AC: 686 AN: 4820

European-Finnish (FIN) AF: 0.0846 AC: 896 AN: 10586

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9081 AN: 68008

Other (OTH) AF: 0.142 AC: 299 AN: 2112

Alfa AF: 0.129 Hom.: 3214

Bravo AF: 0.104

TwinsUK AF: 0.141 AC: 522

ALSPAC AF: 0.128 AC: 495

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.139 AC: 1198

ExAC AF: 0.127 AC: 15422

Asia WGS AF: 0.159 AC: 551 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.156

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	AMTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0021	T
Eigen	Benign	0.077
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.063
Sift	Benign	0.057	T
Sift4G	Benign	0.068	T
Polyphen		0.92	P
Vest4		0.12
MPC		0.18
ClinPred		0.0094	T
GERP RS		4.9
PromoterAI		-0.037	Neutral
Varity_R		0.13
gMVP		0.15
Mutation Taster		=81/19	polymorphism (auto)

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: rs35286445; hg19: chr4-71384537; COSMIC: COSV59488601;