dbSNP rs1031734291: KAZN:p.Ala74Thr (chr1-14599217-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAZN	NM_201628.3 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 1 of 15	ENST00000376030.7	NP_963922.2	Q674X7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KAZN	ENST00000376030.7 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 1 of 15	5	NM_201628.3	ENSP00000365198.2	Q674X7-1
KAZN	ENST00000503743.5 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 2 of 9	1		ENSP00000426015.1	Q674X7-2
KAZN	ENST00000636203.1 link	c.484G>A	p.Ala162Thr	missense_variant	Exon 3 of 17	5		ENSP00000490958.1	A0A1B0GWK2
KAZN	ENST00000491547.1 link	n.514G>A		non_coding_transcript_exon_variant	Exon 1 of 7	2

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.91e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0050

.;T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.33

T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.25

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.13

.;T;T

Sift4G

Benign

0.47

.;T;T

Polyphen

0.028, 0.040

.;B;B

Vest4

0.098, 0.13

MutPred

0.13

.;Gain of glycosylation at A74 (P = 0.0595);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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over