1-26951628-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_152365.3 (KDF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 3655049
• 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 id is 375476.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDF1	NM_152365.3	c.753C>A	p.Phe251Leu	missense_variant	Exon 2 of 4	ENST00000320567.6	NP_689578.2
KDF1	XM_005245735.3	c.753C>A	p.Phe251Leu	missense_variant	Exon 2 of 4		XP_005245792.1
KDF1	XM_011540622.3	c.753C>A	p.Phe251Leu	missense_variant	Exon 2 of 4		XP_011538924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDF1	ENST00000320567.6	c.753C>A	p.Phe251Leu	missense_variant	Exon 2 of 4	2	NM_152365.3	ENSP00000319179.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type Pathogenic:1

Feb 06, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs1057519508; hg19: chr1-27278119;