Genetic Variant KAZN:p.Ala74Thr (chr1-14599217-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_201628.3(KAZN):c.220G>A(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,241,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A74S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

KAZN
NM_201628.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.50

Publications

0 publications found

Variant links:

Genes affected

KAZN (HGNC:29173): (kazrin, periplakin interacting protein) This gene encodes a protein that plays a role in desmosome assembly, cell adhesion, cytoskeletal organization, and epidermal differentiation. This protein co-localizes with desmoplakin and the cytolinker protein periplakin. In general, this protein localizes to the nucleus, desmosomes, cell membrane, and cortical actin-based structures. Some isoforms of this protein also associate with microtubules. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity has not been verified. [provided by RefSeq, Aug 2011]

KAZN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12750924).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201628.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KAZN	NM_201628.3	MANE Select	c.220G>A	p.Ala74Thr	missense	Exon 1 of 15	NP_963922.2	Q674X7-1
KAZN	NM_001437721.1		c.220G>A	p.Ala74Thr	missense	Exon 2 of 9	NP_001424650.1
KAZN	NM_015209.3		c.220G>A	p.Ala74Thr	missense	Exon 1 of 8	NP_056024.1	Q674X7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KAZN	ENST00000376030.7	TSL:5 MANE Select	c.220G>A	p.Ala74Thr	missense	Exon 1 of 15	ENSP00000365198.2	Q674X7-1
KAZN	ENST00000503743.5	TSL:1	c.220G>A	p.Ala74Thr	missense	Exon 2 of 9	ENSP00000426015.1	Q674X7-2
KAZN	ENST00000636203.1	TSL:5	c.484G>A	p.Ala162Thr	missense	Exon 3 of 17	ENSP00000490958.1	A0A1B0GWK2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.05e-7

AC:

AN:

1241634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608198

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25186

American (AMR)

AF:

0.00

AC:

AN:

14700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18586

East Asian (EAS)

AF:

0.00

AC:

AN:

29272

South Asian (SAS)

AF:

0.00

AC:

AN:

49018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3496

European-Non Finnish (NFE)

AF:

9.91e-7

AC:

AN:

1009066

Other (OTH)

AF:

0.00

AC:

AN:

50274

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0050

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

3.5

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.25

REVEL

Benign

0.13

Sift

Benign

0.13

Sift4G

Benign

0.47

Polyphen

0.028

Vest4

0.098

MutPred

0.13

Gain of glycosylation at A74 (P = 0.0595)

MVP

0.37

MPC

0.68

ClinPred

0.32

GERP RS

3.8

Varity_R

0.063

gMVP

0.097

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over