rs141384720

Variant names:

• chr4-70602628-CAGG-C
• rs141384720
• NM_016519.6:c.539_541delGAG

Your query was ambiguous. Multiple possible variants found:

• chr4-70602628-CAGG-C
• chr4-70602628-CAGG-CAGGAGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BA1

The NM_016519.6(AMBN):​c.539_541delGAG​(p.Gly180del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 1,568,758 control chromosomes in the GnomAD database, including 4,446 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.094 (770 hom., cov: 31)
  • Exomes 𝑓: 0.066 (3676 hom.)
• Consequence: AMBN NM_016519.6 disruptive_inframe_deletion
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.390
• Publications: 5 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: AR, SD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• amelogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016519.6. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 4-70602628-CAGG-C is Benign according to our data. Variant chr4-70602628-CAGG-C is described in ClinVar as Benign. ClinVar VariationId is 3056626.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBN	NM_016519.6	MANE Select	c.539_541delGAG	p.Gly180del	disruptive_inframe_deletion	Exon 7 of 13	NP_057603.1	Q9NP70-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBN	ENST00000322937.10	TSL:1 MANE Select	c.539_541delGAG	p.Gly180del	disruptive_inframe_deletion	Exon 7 of 13	ENSP00000313809.6	Q9NP70-1
	AMBN	ENST00000449493.2	TSL:5	c.494_496delGAG	p.Gly165del	disruptive_inframe_deletion	Exon 7 of 13	ENSP00000391234.2	Q9NP70-2

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14294 AN: 151800 Hom.: 771 Cov.: 31

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0634

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.0812 AC: 19064 AN: 234774 AF XY: 0.0808

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0678

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0802

GnomAD4 exome AF: 0.0657 AC: 93066 AN: 1416840 Hom.: 3676 AF XY: 0.0670 AC XY: 47123 AN XY: 703444

African (AFR) AF: 0.139 AC: 4442 AN: 32040

American (AMR) AF: 0.0694 AC: 2834 AN: 40846

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3429 AN: 25042

East Asian (EAS) AF: 0.129 AC: 5033 AN: 38986

South Asian (SAS) AF: 0.104 AC: 7864 AN: 75678

European-Finnish (FIN) AF: 0.0642 AC: 3338 AN: 51988

Middle Eastern (MID) AF: 0.135 AC: 745 AN: 5528

European-Non Finnish (NFE) AF: 0.0558 AC: 60773 AN: 1088394

Other (OTH) AF: 0.0790 AC: 4608 AN: 58338

GnomAD4 genome AF: 0.0942 AC: 14305 AN: 151918 Hom.: 770 Cov.: 31 AF XY: 0.0951 AC XY: 7060 AN XY: 74244

African (AFR) AF: 0.140 AC: 5795 AN: 41416

American (AMR) AF: 0.0865 AC: 1320 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 519 AN: 3462

East Asian (EAS) AF: 0.142 AC: 733 AN: 5178

South Asian (SAS) AF: 0.116 AC: 559 AN: 4822

European-Finnish (FIN) AF: 0.0707 AC: 743 AN: 10510

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0634 AC: 4311 AN: 67962

Other (OTH) AF: 0.0994 AC: 210 AN: 2112

Alfa AF: 0.0894 Hom.: 133

Bravo AF: 0.0967

Asia WGS AF: 0.132 AC: 455 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	AMBN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -4

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

Other links and lift over

dbSNP: rs141384720; hg19: chr4-71468345; COSMIC: COSV59826121;