22-29125410-TTT-AGC

Variant names:

• chr22-29125410-TTT-AGC
• NM_001039570.3:c.625_627delTTTinsAGC
• KREMEN1 p.Phe209Ser

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_001039570.3(KREMEN1):​c.625_627delTTTinsAGC​(p.Phe209Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KREMEN1 NM_001039570.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• Publications: 0 publications found

Genes affected

KREMEN1 (HGNC:17550): (kringle containing transmembrane protein 1) This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor that functionally cooperates with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein is a component of a membrane complex that modulates canonical WNT signaling through lipoprotein receptor-related protein 6 (LRP6). It contains extracellular kringle, WSC, and CUB domains. Mutations in this gene result in ectodermal dysplasia. This protein has also been found to be a functional receptor for Coxsackievirus A10 and may be an alternative entry receptor for SARS-CoV-2. [provided by RefSeq, Nov 2021]

KREMEN1 Gene-Disease associations (from GenCC):

• ectodermal dysplasia 13, hair/tooth type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_001039570.3 (KREMEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039570.3. 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
	KREMEN1	NM_001039570.3	MANE Select	c.625_627delTTTinsAGC	p.Phe209Ser	missense	N/A	NP_001034659.2	Q96MU8-3
	KREMEN1	NM_032045.5		c.625_627delTTTinsAGC	p.Phe209Ser	missense	N/A	NP_114434.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KREMEN1	ENST00000400335.9	TSL:1 MANE Select	c.625_627delTTTinsAGC	p.Phe209Ser	missense	N/A	ENSP00000383189.4	Q96MU8-3
	KREMEN1	ENST00000407188.5	TSL:1	c.619_621delTTTinsAGC	p.Phe207Ser	missense	N/A	ENSP00000385431.1	Q96MU8-1
	KREMEN1	ENST00000943422.1		c.799_801delTTTinsAGC	p.Phe267Ser	missense	N/A	ENSP00000613481.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

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: chr22-29521398;