rs202210195

Variant names:

• chr4-87615883-A-C
• rs202210195
• NM_014208.3:c.3221A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-87615883-A-C
• chr4-87615883-A-G
• chr4-87615883-A-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_014208.3(DSPP):​c.3221A>C​(p.Asp1074Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 770,166 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1074G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.00015 (32 hom.)
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• Publications: 0 publications found

Genes affected

DSPP (HGNC:3054): (dentin sialophosphoprotein) This gene encodes a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. The encoded preproprotein is secreted by odontoblasts and proteolytically processed to generate two principal proteins of the dentin extracellular matrix of the tooth, dentin sialoprotein and dentin phosphoprotein. These two protein products may play distinct but related roles in dentin mineralization. Mutations in this gene are associated with dentinogenesis imperfecta and dentin dysplasia. This gene is present in a gene cluster on chromosome 4. Allelic differences due to repeat polymorphisms have been found for this gene. [provided by RefSeq, Jan 2016]

DSPP Gene-Disease associations (from GenCC):

• deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

  Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• dentinogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dentinogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• dentinogenesis imperfecta type 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• dentin dysplasia type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dentin dysplasia type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000249001 (HGNC:58144):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12436953).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000148 (114/770166) while in subpopulation EAS AF = 0.000325 (8/24586). AF 95% confidence interval is 0.000161. There are 32 homozygotes in GnomAdExome4. There are 60 alleles in the male GnomAdExome4 subpopulation. Median coverage is 155. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 114 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3	c.3221A>C	p.Asp1074Ala	missense_variant	Exon 5 of 5	ENST00000651931.1	NP_055023.2
DMP1-AS1	NR_198971.1	n.367-47350T>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.3221A>C	p.Asp1074Ala	missense_variant	Exon 5 of 5		NM_014208.3	ENSP00000498766.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.000148 AC: 114 AN: 770166 Hom.: 32 Cov.: 155 AF XY: 0.000157 AC XY: 60 AN XY: 382452

African (AFR) AF: 0.00 AC: 0 AN: 26718

American (AMR) AF: 0.0000382 AC: 1 AN: 26202

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 2 AN: 17068

East Asian (EAS) AF: 0.000325 AC: 8 AN: 24586

South Asian (SAS) AF: 0.000119 AC: 5 AN: 42042

European-Finnish (FIN) AF: 0.000611 AC: 20 AN: 32756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3744

European-Non Finnish (NFE) AF: 0.000133 AC: 75 AN: 562734

Other (OTH) AF: 0.0000874 AC: 3 AN: 34316

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3221A>C (p.D1074A) alteration is located in exon 5 (coding exon 4) of the DSPP gene. This alteration results from a A to C substitution at nucleotide position 3221, causing the aspartic acid (D) at amino acid position 1074 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.47
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift4G	Benign	0.68	T
Polyphen		0.27	B
Vest4		0.29
MutPred		0.25		Gain of glycosylation at S1070 (P = 4e-04);
MVP		0.69
ClinPred		0.11	T
GERP RS		1.5
Varity_R		0.23
gMVP		0.0011
Mutation Taster		=98/2	polymorphism

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: rs202210195; hg19: chr4-88537035;