9-112574115-T-C

Variant names:

• chr9-112574115-T-C
• NM_133465.4:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_133465.4(KIAA1958):​c.35T>C​(p.Leu12Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 6.81
• Publications: 0 publications found

Genes affected

KIAA1958 (HGNC:23427): (KIAA1958)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA1958	NM_133465.4	c.35T>C	p.Leu12Pro	missense_variant	Exon 2 of 4	ENST00000337530.11	NP_597722.1
KIAA1958	NM_001287036.2	c.35T>C	p.Leu12Pro	missense_variant	Exon 2 of 5		NP_001273965.1
KIAA1958	NM_001287038.2	c.35T>C	p.Leu12Pro	missense_variant	Exon 2 of 4		NP_001273967.1
KIAA1958	XM_011518311.3	c.35T>C	p.Leu12Pro	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.35T>C	p.Leu12Pro	missense_variant	Exon 2 of 4	1	NM_133465.4	ENSP00000336940.6
KIAA1958	ENST00000536272.5	c.35T>C	p.Leu12Pro	missense_variant	Exon 2 of 5	1		ENSP00000440504.1
KIAA1958	ENST00000374244.3	c.35T>C	p.Leu12Pro	missense_variant	Exon 2 of 3	5		ENSP00000363362.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35T>C (p.L12P) alteration is located in exon 2 (coding exon 1) of the KIAA1958 gene. This alteration results from a T to C substitution at nucleotide position 35, causing the leucine (L) at amino acid position 12 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	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.90	L;L;L
PhyloP100		6.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.57	N;N;N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.69		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.69
MPC		1.2
ClinPred		0.76	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.98
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr9-115336395;