1-26950101-A-G

Position:

• chr1-26950101-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152365.3(KDF1):​c.1165T>C​(p.Ser389Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S389S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDF1 NM_152365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDF1	NM_152365.3	c.1165T>C	p.Ser389Pro	missense_variant	4/4	ENST00000320567.6	NP_689578.2
KDF1	XM_005245735.3	c.1165T>C	p.Ser389Pro	missense_variant	4/4		XP_005245792.1
KDF1	XM_011540622.3	c.1165T>C	p.Ser389Pro	missense_variant	4/4		XP_011538924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDF1	ENST00000320567.6	c.1165T>C	p.Ser389Pro	missense_variant	4/4	2	NM_152365.3	ENSP00000319179.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KDF1 protein function. This variant has not been reported in the literature in individuals affected with KDF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 389 of the KDF1 protein (p.Ser389Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.16		Loss of glycosylation at S389 (P = 0.0379);
MVP		0.52
MPC		1.1
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.61
gMVP		0.65

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: chr1-27276592;