1-26951654-T-G

Position:

• chr1-26951654-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_152365.3(KDF1):​c.727A>C​(p.Ile243Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDF1 NM_152365.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.43

Genes affected

KDF1 (HGNC:26624): (keratinocyte differentiation factor 1) Predicted to be involved in several processes, including positive regulation of epidermal cell differentiation; regulation of epidermal cell division; and skin development. Predicted to act upstream of or within keratinocyte development and negative regulation of keratinocyte proliferation. Located in cell junction; mitotic spindle; and nucleoplasm. Implicated in ectodermal dysplasia 12. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-26951654-T-G is Pathogenic according to our data. Variant chr1-26951654-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2581057.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDF1	NM_152365.3	c.727A>C	p.Ile243Leu	missense_variant	2/4	ENST00000320567.6	NP_689578.2
KDF1	XM_005245735.3	c.727A>C	p.Ile243Leu	missense_variant	2/4		XP_005245792.1
KDF1	XM_011540622.3	c.727A>C	p.Ile243Leu	missense_variant	2/4		XP_011538924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDF1	ENST00000320567.6	c.727A>C	p.Ile243Leu	missense_variant	2/4	2	NM_152365.3	ENSP00000319179.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Partial congenital absence of teeth Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University

-

A de novo heterozygous missense variant NM_152365.3: c.727A>C (p.Ile243Leu) in the KDF1 gene was identified in a patient with oligodontia. The missense variants inthis gene were reported in patients with nonsyndromic tooth agenesis (Zeng et al., 2018, Pan et al., 2022). This variant was classified to be likely pathogenic according to ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.21		Loss of methylation at K245 (P = 0.0834);
MVP		0.45
MPC		0.97
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-27278145;