Genetic Variant KIAA1191:p.Arg62His (chr5-176355593-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020444.5(KIAA1191):c.185G>A(p.Arg62His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,610,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KIAA1191
NM_020444.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

Publications

0 publications found

Variant links:

Genes affected

KIAA1191 (HGNC:29209): (KIAA1191) Predicted to enable oxidoreductase activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

KIAA1191 links:

ENSG00000251414 (HGNC:):

ENSG00000251414 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30518782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA1191	NM_020444.5 link	c.185G>A	p.Arg62His	missense_variant	Exon 4 of 9	ENST00000298569.9	NP_065177.2	Q96A73-1A0A024R7Q7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA1191	ENST00000298569.9 link	c.185G>A	p.Arg62His	missense_variant	Exon 4 of 9	1	NM_020444.5	ENSP00000298569.4		Q96A73-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251106

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1458724

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725416

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33384

American (AMR)

AF:

0.0000448

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000126

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4224

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1110986

Other (OTH)

AF:

0.0000166

AC:

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41412

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.185G>A (p.R62H) alteration is located in exon 4 (coding exon 2) of the KIAA1191 gene. This alteration results from a G to A substitution at nucleotide position 185, causing the arginine (R) at amino acid position 62 to be replaced by a histidine (H). 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

0.12

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

T;.;.;T;T;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

.;.;T;T;T;T;T

M_CAP

Benign

0.0089

MetaRNN

Benign

0.31

T;T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

M;.;.;M;.;.;.

PhyloP100

5.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.1

N;N;.;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.15

T;T;.;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;.;D;.

Polyphen

0.48

P;.;.;P;.;.;.

Vest4

0.79

MutPred

0.45

Loss of ubiquitination at K63 (P = 0.0675);.;.;Loss of ubiquitination at K63 (P = 0.0675);.;.;.;

MVP

0.73

MPC

0.39

ClinPred

0.12

GERP RS

5.1

Varity_R

0.24

gMVP

0.34

Mutation Taster

=57/43

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

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5-176355593-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over