Genetic Variant NM_133465.4:c.131T>G (chr9-112574211-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_133465.4(KIAA1958):c.131T>G(p.Leu44Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KIAA1958
NM_133465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

Publications

0 publications found

Variant links:

Genes affected

KIAA1958 (HGNC:23427): (KIAA1958)

KIAA1958 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA1958	NM_133465.4 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 4	ENST00000337530.11	NP_597722.1	Q8N8K9-1
KIAA1958	NM_001287036.2 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 5		NP_001273965.1	Q8N8K9-3
KIAA1958	NM_001287038.2 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 4		NP_001273967.1	Q8N8K9
KIAA1958	XM_011518311.3 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 3		XP_011516613.1	Q8N8K9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KIAA1958	ENST00000337530.11 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 4	1	NM_133465.4	ENSP00000336940.6	Q8N8K9-1
KIAA1958	ENST00000536272.5 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 5	1		ENSP00000440504.1	Q8N8K9-3
KIAA1958	ENST00000374244.3 link	c.131T>G	p.Leu44Arg	missense_variant	Exon 2 of 3	5		ENSP00000363362.3	Q8N8K9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

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

Mar 16, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.131T>G (p.L44R) alteration is located in exon 2 (coding exon 1) of the KIAA1958 gene. This alteration results from a T to G substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by an arginine (R). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.051

T;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.90

L;L;L

PhyloP100

5.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.90

N;N;N

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MVP

0.45

MPC

1.1

ClinPred

0.80

GERP RS

4.9

Varity_R

0.66

gMVP

0.82

Mutation Taster

=49/51

disease causing

(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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NM_133465.4:c.131T>G

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