22-45205691-G-C

Position:

• chr22-45205691-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001009880.2(KIAA0930):​c.353C>G​(p.Thr118Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KIAA0930 NM_001009880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.71

Genes affected

KIAA0930 (HGNC:1314): (KIAA0930)

KIAA0930 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0930	NM_001009880.2	c.353C>G	p.Thr118Ser	missense_variant	4/10	ENST00000336156.10	NP_001009880.1
KIAA0930	NM_015264.2	c.368C>G	p.Thr123Ser	missense_variant	4/10		NP_056079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0930	ENST00000336156.10	c.353C>G	p.Thr118Ser	missense_variant	4/10	1	NM_001009880.2	ENSP00000336720.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

Bravo AF: 0.00000378

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

Mar 28, 2024

The c.368C>G (p.T123S) alteration is located in exon 4 (coding exon 4) of the KIAA0930 gene. This alteration results from a C to G substitution at nucleotide position 368, causing the threonine (T) at amino acid position 123 to be replaced by a serine (S). 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	0.64
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.4	L;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.074	T;T;T;.;T
Polyphen		0.058	B;B;.;.;.
Vest4		0.86
MutPred		0.85		Loss of sheet (P = 0.0357);.;.;.;.;
MVP		0.26
MPC		0.45
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2083630594; hg19: chr22-45601572;