4-70605459-G-T

Variant names:

• chr4-70605459-G-T
• rs34538475
• NM_016519.6:c.799-726G>T

Variant summary

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

The NM_016519.6(AMBN):​c.799-726G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 151,998 control chromosomes in the GnomAD database, including 4,721 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4721 hom., cov: 32)
• Consequence: AMBN NM_016519.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016519.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBN	NM_016519.6	MANE Select	c.799-726G>T		intron	N/A	NP_057603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBN	ENST00000322937.10	TSL:1 MANE Select	c.799-726G>T		intron	N/A	ENSP00000313809.6
	AMBN	ENST00000449493.2	TSL:5	c.754-726G>T		intron	N/A	ENSP00000391234.2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36201 AN: 151880 Hom.: 4715 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.198

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.238 AC: 36227 AN: 151998 Hom.: 4721 Cov.: 32 AF XY: 0.229 AC XY: 17029 AN XY: 74278

African (AFR) AF: 0.266 AC: 11041 AN: 41430

American (AMR) AF: 0.159 AC: 2434 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3472

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5184

South Asian (SAS) AF: 0.105 AC: 504 AN: 4810

European-Finnish (FIN) AF: 0.194 AC: 2044 AN: 10552

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18857 AN: 67944

Other (OTH) AF: 0.195 AC: 412 AN: 2108

Alfa AF: 0.233 Hom.: 1894

Bravo AF: 0.236

Asia WGS AF: 0.0780 AC: 273 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.34
PhyloP100		-1.0
Mutation Taster		=100/0	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: rs34538475; hg19: chr4-71471176;