chr9-112574723-G-A

Variant names:

• chr9-112574723-G-A
• NM_133465.4:c.643G>A

Variant summary

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

The NM_133465.4(KIAA1958):​c.643G>A​(p.Ala215Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 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	c.643G>A	p.Ala215Thr	missense_variant	Exon 2 of 4	ENST00000337530.11	NP_597722.1
KIAA1958	NM_001287036.2	c.643G>A	p.Ala215Thr	missense_variant	Exon 2 of 5		NP_001273965.1
KIAA1958	NM_001287038.2	c.643G>A	p.Ala215Thr	missense_variant	Exon 2 of 4		NP_001273967.1
KIAA1958	XM_011518311.3	c.643G>A	p.Ala215Thr	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.643G>A	p.Ala215Thr	missense_variant	Exon 2 of 4	1	NM_133465.4	ENSP00000336940.6
KIAA1958	ENST00000536272.5	c.643G>A	p.Ala215Thr	missense_variant	Exon 2 of 5	1		ENSP00000440504.1
KIAA1958	ENST00000374244.3	c.643G>A	p.Ala215Thr	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

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643G>A (p.A215T) alteration is located in exon 2 (coding exon 1) of the KIAA1958 gene. This alteration results from a G to A substitution at nucleotide position 643, causing the alanine (A) at amino acid position 215 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	0.33
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.066	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	L;L;L
PhyloP100		7.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.51	N;N;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.63
MutPred		0.28		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.83
MPC		0.83
ClinPred		0.77	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.49
Mutation Taster		=41/59	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: chr9-115337003;