9-112574657-G-A

Variant names:

• chr9-112574657-G-A
• rs536455762
• NM_133465.4:c.577G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_133465.4(KIAA1958):​c.577G>A​(p.Glu193Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,614,126 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: KIAA1958 NM_133465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01
• Publications: 0 publications found

Genes affected

KIAA1958 (HGNC:23427): (KIAA1958)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026916057).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA1958	NM_133465.4	c.577G>A	p.Glu193Lys	missense_variant	Exon 2 of 4	ENST00000337530.11	NP_597722.1
KIAA1958	NM_001287036.2	c.577G>A	p.Glu193Lys	missense_variant	Exon 2 of 5		NP_001273965.1
KIAA1958	NM_001287038.2	c.577G>A	p.Glu193Lys	missense_variant	Exon 2 of 4		NP_001273967.1
KIAA1958	XM_011518311.3	c.577G>A	p.Glu193Lys	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.577G>A	p.Glu193Lys	missense_variant	Exon 2 of 4	1	NM_133465.4	ENSP00000336940.6
KIAA1958	ENST00000536272.5	c.577G>A	p.Glu193Lys	missense_variant	Exon 2 of 5	1		ENSP00000440504.1
KIAA1958	ENST00000374244.3	c.577G>A	p.Glu193Lys	missense_variant	Exon 2 of 3	5		ENSP00000363362.3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251254 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1461880 Hom.: 3 Cov.: 33 AF XY: 0.000193 AC XY: 140 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111998

Other (OTH) AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.577G>A (p.E193K) 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 577, causing the glutamic acid (E) at amino acid position 193 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;L
PhyloP100		6.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.94	P;.;.
Vest4		0.40
MutPred		0.38		Gain of methylation at E193 (P = 4e-04);Gain of methylation at E193 (P = 4e-04);Gain of methylation at E193 (P = 4e-04);
MVP		0.73
MPC		0.30
ClinPred		0.17	T
GERP RS		6.1
Varity_R		0.12
gMVP		0.33
Mutation Taster		=82/18	polymorphism

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

dbSNP: rs536455762; hg19: chr9-115336937; COSMIC: COSV61728445;