4-70602623-G-A

Variant names:

• chr4-70602623-G-A
• rs146238585
• NM_016519.6:c.532-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_016519.6(AMBN):​c.532-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000384 in 1,564,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: AMBN NM_016519.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.27
• Publications: 4 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 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029017856 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of 7, new splice context is: atctgtgatataactcccAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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.532-1G>A		splice_acceptor 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.532-1G>A		splice_acceptor intron	N/A	ENSP00000313809.6
	AMBN	ENST00000449493.2	TSL:5	c.487-1G>A		splice_acceptor intron	N/A	ENSP00000391234.2

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 229080 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000613

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1414748 Hom.: 0 Cov.: 29 AF XY: 0.00000427 AC XY: 3 AN XY: 702230

African (AFR) AF: 0.00 AC: 0 AN: 31972

American (AMR) AF: 0.00 AC: 0 AN: 40106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24936

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39008

South Asian (SAS) AF: 0.00 AC: 0 AN: 74798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1088318

Other (OTH) AF: 0.00 AC: 0 AN: 58252

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73060

African (AFR) AF: 0.00 AC: 0 AN: 40238

American (AMR) AF: 0.00 AC: 0 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67666

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	26
DANN	Uncertain	0.98
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.73	D
PhyloP100		4.3
GERP RS		3.6
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 8
DS_AL_spliceai		0.70		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146238585; hg19: chr4-71468340;