NM_016519.6:c.488T>C

Variant names:

• chr4-70601611-T-C
• rs1055383957
• NM_016519.6:c.488T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016519.6(AMBN):​c.488T>C​(p.Val163Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AMBN NM_016519.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070981234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.488T>C	p.Val163Ala	missense_variant	Exon 6 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.488T>C	p.Val163Ala	missense_variant	Exon 6 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.443T>C	p.Val148Ala	missense_variant	Exon 6 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250826 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.8
DANN	Benign	0.62
DEOGEN2	Benign	0.028	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.33	T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.57	N;.;N
REVEL	Benign	0.0090
Sift	Benign	0.21	T;.;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.074
MutPred		0.36		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;
MVP		0.21
MPC		0.067
ClinPred		0.035	T
GERP RS		0.30
Varity_R		0.042
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs1055383957; hg19: chr4-71467328;