rs2306175

Variant names:

• chr4-75564135-C-T
• rs2306175
• NM_178497.5:c.89C>T
• ODAPH p.Pro30Leu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178497.5(ODAPH):​c.89C>T​(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,544 control chromosomes in the GnomAD database, including 44,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4691 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40270 hom.)
• Consequence: ODAPH NM_178497.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.96
• Publications: 20 publications found

Genes affected

ODAPH (HGNC:26300): (odontogenesis associated phosphoprotein) Dental enamel forms the outer cap of teeth and is the hardest substance found in vertebrates. This gene is thought to encode an extracellular matrix acidic phosphoprotein that has a function in enamel mineralization during amelogenesis. Mutations in this gene are associated with recessive hypomineralized amelogenesis imperfecta. [provided by RefSeq, Oct 2012]

ODAPH Gene-Disease associations (from GenCC):

• amelogenesis imperfecta hypomaturation type 2A4

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005912304).
• BP6: Variant 4-75564135-C-T is Benign according to our data. Variant chr4-75564135-C-T is described in ClinVar as Benign. ClinVar VariationId is 262959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178497.5. 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
	ODAPH	NM_178497.5	MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 2 of 2	NP_848592.2	Q17RF5-1
	ODAPH	NM_001206981.2		c.133C>T	p.Leu45Phe	missense	Exon 3 of 3	NP_001193910.1	Q17RF5-2
	ODAPH	NM_001257072.2		c.89C>T	p.Pro30Leu	missense	Exon 2 of 3	NP_001244001.1	A0A087WV33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAPH	ENST00000311623.9	TSL:1 MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 2 of 2	ENSP00000311307.5	Q17RF5-1
	ODAPH	ENST00000511093.5	TSL:1	n.*102C>T		non_coding_transcript_exon	Exon 3 of 4	ENSP00000421429.1	D6RFW7
	ODAPH	ENST00000511093.5	TSL:1	n.*102C>T		3_prime_UTR	Exon 3 of 4	ENSP00000421429.1	D6RFW7

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36785 AN: 151942 Hom.: 4682 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.215 AC: 54175 AN: 251406 AF XY: 0.217

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.247

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.232 AC: 338657 AN: 1461484 Hom.: 40270 Cov.: 34 AF XY: 0.231 AC XY: 167753 AN XY: 727080

African (AFR) AF: 0.304 AC: 10181 AN: 33474

American (AMR) AF: 0.123 AC: 5503 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3919 AN: 26134

East Asian (EAS) AF: 0.277 AC: 11000 AN: 39700

South Asian (SAS) AF: 0.204 AC: 17590 AN: 86248

European-Finnish (FIN) AF: 0.251 AC: 13412 AN: 53412

Middle Eastern (MID) AF: 0.148 AC: 852 AN: 5768

European-Non Finnish (NFE) AF: 0.236 AC: 262892 AN: 1111644

Other (OTH) AF: 0.220 AC: 13308 AN: 60380

GnomAD4 genome AF: 0.242 AC: 36824 AN: 152060 Hom.: 4691 Cov.: 32 AF XY: 0.240 AC XY: 17859 AN XY: 74322

African (AFR) AF: 0.300 AC: 12419 AN: 41460

American (AMR) AF: 0.175 AC: 2672 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3472

East Asian (EAS) AF: 0.248 AC: 1285 AN: 5172

South Asian (SAS) AF: 0.206 AC: 995 AN: 4820

European-Finnish (FIN) AF: 0.254 AC: 2683 AN: 10554

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15621 AN: 67982

Other (OTH) AF: 0.212 AC: 448 AN: 2112

Alfa AF: 0.230 Hom.: 16006

Bravo AF: 0.237

Asia WGS AF: 0.233 AC: 812 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.221

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.0
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.25	T
Sift4G	Benign	0.37	T
Varity_R		0.19
gMVP		0.016
Mutation Taster		=93/7	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2306175;

hg19: chr4-76489345;

COSMIC: COSV61140988;

COSMIC: COSV61140988;