4-70598367-G-C

Variant names:

• chr4-70598367-G-C
• rs867402927
• NM_016519.6:c.147G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016519.6(AMBN):​c.147G>C​(p.Gln49His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AMBN NM_016519.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.311

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.147G>C	p.Gln49His	missense_variant	Exon 4 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.147G>C	p.Gln49His	missense_variant	Exon 4 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.147G>C	p.Gln49His	missense_variant	Exon 4 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.147G>C (p.Q49H) alteration is located in exon 4 (coding exon 4) of the AMBN gene. This alteration results from a G to C substitution at nucleotide position 147, causing the glutamine (Q) at amino acid position 49 to be replaced by a histidine (H). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;.;D
REVEL	Benign	0.24
Sift	Benign	0.057	T;.;T
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.57
MutPred		0.91		Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);
MVP		0.48
MPC		0.19
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs867402927; hg19: chr4-71464084; COSMIC: COSV100534409;