Genetic Variant SKIC8:p.Ile99Met (chr15-78292638-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025234.3(SKIC8):c.297A>G(p.Ile99Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000025 ( 0 hom. )

Consequence

SKIC8
NM_025234.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.195

Variant links:

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]

SKIC8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16881135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC8	NM_025234.3 link	c.297A>G	p.Ile99Met	missense_variant	Exon 5 of 11	ENST00000267973.7	NP_079510.1	Q9GZS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC8	ENST00000267973.7 link	c.297A>G	p.Ile99Met	missense_variant	Exon 5 of 11	1	NM_025234.3	ENSP00000267973.2		Q9GZS3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251446

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.297A>G (p.I99M) alteration is located in exon 5 (coding exon 4) of the WDR61 gene. This alteration results from a A to G substitution at nucleotide position 297, causing the isoleucine (I) at amino acid position 99 to be replaced by a methionine (M). 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

0.078

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.068

T;T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.84

.;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.24

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.17

MutPred

0.29

Gain of disorder (P = 0.0602);Gain of disorder (P = 0.0602);Gain of disorder (P = 0.0602);

MVP

0.64

MPC

0.57

ClinPred

0.049

GERP RS

-10

Varity_R

0.20

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over