1-26951518-A-G

Variant names:

• chr1-26951518-A-G
• NM_152365.3:c.863T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152365.3(KDF1):​c.863T>C​(p.Leu288Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDF1 NM_152365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

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]

KDF1 Gene-Disease associations (from GenCC):

• ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal dominant hypohidrotic ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152365.3. 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
	KDF1	NM_152365.3	MANE Select	c.863T>C	p.Leu288Pro	missense	Exon 2 of 4	NP_689578.2	Q8NAX2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDF1	ENST00000320567.6	TSL:2 MANE Select	c.863T>C	p.Leu288Pro	missense	Exon 2 of 4	ENSP00000319179.5	Q8NAX2
	KDF1	ENST00000866899.1		c.863T>C	p.Leu288Pro	missense	Exon 2 of 4	ENSP00000536958.1
	KDF1	ENST00000866900.1		c.863T>C	p.Leu288Pro	missense	Exon 3 of 5	ENSP00000536959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.9
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.91
gMVP		0.82
Mutation Taster		=34/66	disease causing

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

hg19: chr1-27278009;