1-14599136-G-A

Variant names:

• chr1-14599136-G-A
• rs775963111
• NM_201628.3:c.139G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201628.3(KAZN):​c.139G>A​(p.Gly47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G47R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KAZN NM_201628.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

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]

ACMG classification

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=0.1101678).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZN	NM_201628.3	MANE Select	c.139G>A	p.Gly47Ser	missense	Exon 1 of 15	NP_963922.2	Q674X7-1
	KAZN	NM_001437721.1		c.139G>A	p.Gly47Ser	missense	Exon 2 of 9	NP_001424650.1
	KAZN	NM_015209.3		c.139G>A	p.Gly47Ser	missense	Exon 1 of 8	NP_056024.1	Q674X7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZN	ENST00000376030.7	TSL:5 MANE Select	c.139G>A	p.Gly47Ser	missense	Exon 1 of 15	ENSP00000365198.2	Q674X7-1
	KAZN	ENST00000503743.5	TSL:1	c.139G>A	p.Gly47Ser	missense	Exon 2 of 9	ENSP00000426015.1	Q674X7-2
	KAZN	ENST00000636203.1	TSL:5	c.403G>A	p.Gly135Ser	missense	Exon 3 of 17	ENSP00000490958.1	A0A1B0GWK2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151748 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1303314 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 643962

African (AFR) AF: 0.00 AC: 0 AN: 25844

American (AMR) AF: 0.00 AC: 0 AN: 18432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20884

East Asian (EAS) AF: 0.00 AC: 0 AN: 30778

South Asian (SAS) AF: 0.00 AC: 0 AN: 61194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041528

Other (OTH) AF: 0.00 AC: 0 AN: 52942

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151748 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74102

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.22	N
REVEL	Benign	0.054
Sift	Benign	0.41	T
Sift4G	Benign	0.37	T
Polyphen		0.038	B
Vest4		0.19
MutPred		0.18		Gain of glycosylation at G47 (P = 0.0028)
MVP		0.19
MPC		1.7
ClinPred		0.40	T
GERP RS		2.5
PromoterAI		-0.035	Neutral
Varity_R		0.075
gMVP		0.10
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs775963111; hg19: chr1-14925632;