Genetic Variant KATNA1:p.Arg135Thr (chr6-149623200-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007044.4(KATNA1):c.404G>C(p.Arg135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,748 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

KATNA1
NM_007044.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

KATNA1 (HGNC:6216): (katanin catalytic subunit A1) Microtubules, polymers of alpha and beta tubulin subunits, form the mitotic spindle of a dividing cell and help to organize membranous organelles during interphase. Katanin is a heterodimer that consists of a 60 kDa ATPase (p60 subunit A 1) and an 80 kDa accessory protein (p80 subunit B 1). The p60 subunit acts to sever and disassemble microtubules, while the p80 subunit targets the enzyme to the centrosome. This gene encodes the p80 subunit. This protein is a member of the AAA family of ATPases. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Feb 2011]

KATNA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026744872).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KATNA1	NM_007044.4 link	c.404G>C	p.Arg135Thr	missense_variant	Exon 4 of 11	ENST00000367411.7	NP_008975.1	O75449-1A8K7S5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KATNA1	ENST00000367411.7 link	c.404G>C	p.Arg135Thr	missense_variant	Exon 4 of 11	2	NM_007044.4	ENSP00000356381.2		O75449-1

Frequencies

GnomAD3 genomes

AF:

0.000960

AC:

146

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000991

AC:

249

AN:

251218

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00154

AC:

2251

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1079

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00191

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000959

AC:

146

AN:

152244

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00146

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00127

AC:

154

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404G>C (p.R135T) alteration is located in exon 4 (coding exon 3) of the KATNA1 gene. This alteration results from a G to C substitution at nucleotide position 404, causing the arginine (R) at amino acid position 135 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.022

T;.;T;T;T

Eigen

Benign

-0.032

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

.;T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Uncertain

-0.044

MutationAssessor

Uncertain

2.3

M;M;M;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.12

N;N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.20

T;T;T;T;D

Sift4G

Benign

0.13

T;T;T;.;T

Polyphen

0.0010

B;B;B;.;.

Vest4

0.53

MVP

0.97

MPC

0.70

ClinPred

0.015

GERP RS

4.9

Varity_R

0.12

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over