4-70603887-C-G

Variant names:

• chr4-70603887-C-G
• rs7439186
• NM_016519.6:c.764C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016519.6(AMBN):​c.764C>G​(p.Ala255Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A255V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMBN NM_016519.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.878
• Publications: 18 publications found

Genes affected

AMBN (HGNC:452): (ameloblastin) This gene encodes the nonamelogenin enamel matrix protein ameloblastin. The encoded protein may be important in enamel matrix formation and mineralization. This gene is located in the calcium-binding phosphoprotein gene cluster on chromosome 4. Mutations in this gene may be associated with dentinogenesis imperfect and autosomal dominant amylogenesis imperfect. [provided by RefSeq, Aug 2011]

AMBN Gene-Disease associations (from GenCC):

• amelogenesis imperfecta type 1F

  Inheritance: SD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20186105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.764C>G	p.Ala255Gly	missense_variant	Exon 12 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.764C>G	p.Ala255Gly	missense_variant	Exon 12 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.719C>G	p.Ala240Gly	missense_variant	Exon 12 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.;.
PhyloP100		-0.88
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.027
Sift	Benign	0.062	T;.;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.020	B;.;.
Vest4		0.28
MutPred		0.56		Gain of loop (P = 0.069);.;.;
MVP		0.26
MPC		0.072
ClinPred		0.081	T
GERP RS		-0.77
Varity_R		0.098
gMVP		0.047
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7439186; hg19: chr4-71469604;