4-70597004-T-A

Variant names:

• chr4-70597004-T-A
• NM_016519.6:c.90T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016519.6(AMBN):​c.90T>A​(p.Phe30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMBN NM_016519.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.90T>A	p.Phe30Leu	missense_variant	Exon 3 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.90T>A	p.Phe30Leu	missense_variant	Exon 3 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.90T>A	p.Phe30Leu	missense_variant	Exon 3 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.90T>A (p.F30L) alteration is located in exon 3 (coding exon 3) of the AMBN gene. This alteration results from a T to A substitution at nucleotide position 90, causing the phenylalanine (F) at amino acid position 30 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.024	D;.;D
Sift4G	Uncertain	0.060	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.68
MutPred		0.69		Loss of glycosylation at P28 (P = 0.0672);Loss of glycosylation at P28 (P = 0.0672);Loss of glycosylation at P28 (P = 0.0672);
MVP		0.55
MPC		0.34
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-71462721;