chr9-112574540-A-C

Variant names:

• chr9-112574540-A-C
• NM_133465.4:c.460A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133465.4(KIAA1958):​c.460A>C​(p.Thr154Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIAA1958 NM_133465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• Publications: 0 publications found

Genes affected

KIAA1958 (HGNC:23427): (KIAA1958)

ACMG classification

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=0.32247573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA1958	NM_133465.4	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 4	ENST00000337530.11	NP_597722.1
KIAA1958	NM_001287036.2	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 5		NP_001273965.1
KIAA1958	NM_001287038.2	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 4		NP_001273967.1
KIAA1958	XM_011518311.3	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 3		XP_011516613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA1958	ENST00000337530.11	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 4	1	NM_133465.4	ENSP00000336940.6
KIAA1958	ENST00000536272.5	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 5	1		ENSP00000440504.1
KIAA1958	ENST00000374244.3	c.460A>C	p.Thr154Pro	missense_variant	Exon 2 of 3	5		ENSP00000363362.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.460A>C (p.T154P) alteration is located in exon 2 (coding exon 1) of the KIAA1958 gene. This alteration results from a A to C substitution at nucleotide position 460, causing the threonine (T) at amino acid position 154 to be replaced by a proline (P). 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	0.77
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	L;L;L
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.48
MutPred		0.12		Loss of phosphorylation at T154 (P = 0.0206);Loss of phosphorylation at T154 (P = 0.0206);Loss of phosphorylation at T154 (P = 0.0206);
MVP		0.87
MPC		1.0
ClinPred		0.79	D
GERP RS		6.1
Varity_R		0.41
gMVP		0.38
Mutation Taster		=45/55	disease causing

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

hg19: chr9-115336820;