15-78283437-T-C

Variant names:

• chr15-78283437-T-C
• NM_025234.3:c.913A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025234.3(SKIC8):​c.913A>G​(p.Ile305Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SKIC8 NM_025234.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0220

Genes affected

SKIC8 (HGNC:30300): (SKI8 subunit of superkiller complex) WDR61 is a subunit of the human PAF and SKI complexes, which function in transcriptional regulation and are involved in events downstream of RNA synthesis, such as RNA surveillance (Zhu et al., 2005 [PubMed 16024656]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03436342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC8	NM_025234.3	c.913A>G	p.Ile305Val	missense_variant	Exon 11 of 11	ENST00000267973.7	NP_079510.1
SKIC8	NM_001303247.2	c.913A>G	p.Ile305Val	missense_variant	Exon 11 of 11		NP_001290176.1
SKIC8	NM_001303248.2	c.634A>G	p.Ile212Val	missense_variant	Exon 9 of 9		NP_001290177.1
SKIC8	XM_011522094.3	c.913A>G	p.Ile305Val	missense_variant	Exon 11 of 11		XP_011520396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC8	ENST00000267973.7	c.913A>G	p.Ile305Val	missense_variant	Exon 11 of 11	1	NM_025234.3	ENSP00000267973.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461004 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726844

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.913A>G (p.I305V) alteration is located in exon 11 (coding exon 10) of the WDR61 gene. This alteration results from a A to G substitution at nucleotide position 913, causing the isoleucine (I) at amino acid position 305 to be replaced by a valine (V). 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	0.055
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.94
DANN	Benign	0.86
DEOGEN2	Benign	0.056	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.090
MutPred		0.51		Gain of catalytic residue at I305 (P = 0.0388);Gain of catalytic residue at I305 (P = 0.0388);.;
MVP		0.29
MPC		0.46
ClinPred		0.028	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.098

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-78575779;