16-85086645-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001388359.1(KIAA0513):c.1012G>C(p.Glu338Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KIAA0513 NM_001388359.1 missense, splice_region
• Scores: Splicing: ADA: 0.9335
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.41

Genes affected

KIAA0513 (HGNC:29058): (KIAA0513) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34056085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0513	NM_001388359.1	c.1012G>C	p.Glu338Gln	missense_variant, splice_region_variant	11/13	ENST00000683363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0513	ENST00000683363.1	c.1012G>C	p.Glu338Gln	missense_variant, splice_region_variant	11/13		NM_001388359.1	A1
KIAA0513	ENST00000566428.5	c.1012G>C	p.Glu338Gln	missense_variant, splice_region_variant	11/13	1		A1
KIAA0513	ENST00000538274.6	c.982G>C	p.Glu328Gln	missense_variant, splice_region_variant	10/12	2		P4
KIAA0513	ENST00000562564.1	c.118G>C	p.Glu40Gln	missense_variant, splice_region_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461362 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.1012G>C (p.E338Q) alteration is located in exon 11 (coding exon 10) of the KIAA0513 gene. This alteration results from a G to C substitution at nucleotide position 1012, causing the glutamic acid (E) at amino acid position 338 to be replaced by a glutamine (Q). 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	0.23
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;.;D;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.86	N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.054	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.78	P;.;P;.;.
Vest4		0.61
MutPred		0.37		Gain of methylation at K339 (P = 0.0854);.;Gain of methylation at K339 (P = 0.0854);.;.;
MVP		0.51
MPC		0.25
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368263054; hg19: chr16-85120251;