rs1057519508

Variant names:

• chr1-26951628-G-T
• rs1057519508
• NM_152365.3:c.753C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-26951628-G-T
• chr1-26951628-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3 PP5

The NM_152365.3(KDF1):​c.753C>A​(p.Phe251Leu) variant causes a missense change. 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 Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDF1 NM_152365.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.21
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_152365.3 (KDF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• PP5: Variant 1-26951628-G-T is Pathogenic according to our data. Variant chr1-26951628-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375476.Status of the report is no_assertion_criteria_provided, 0 stars.

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.753C>A	p.Phe251Leu	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.753C>A	p.Phe251Leu	missense	Exon 2 of 4	ENSP00000319179.5	Q8NAX2
	KDF1	ENST00000866899.1		c.753C>A	p.Phe251Leu	missense	Exon 2 of 4	ENSP00000536958.1
	KDF1	ENST00000866900.1		c.753C>A	p.Phe251Leu	missense	Exon 3 of 5	ENSP00000536959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.2
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.34		Loss of ubiquitination at K246 (P = 0.0709)
MVP		0.43
MPC		1.1
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.66
gMVP		0.37
Mutation Taster		=25/75	disease causing (ClinVar)

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: rs1057519508; hg19: chr1-27278119;