NM_014639.4:c.4655C>G

Variant names:

• chr5-95464647-G-C
• NM_014639.4:c.4655C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014639.4(SKIC3):​c.4655C>G​(p.Thr1552Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1552P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SKIC3 NM_014639.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.702
• Publications: 0 publications found

Genes affected

SKIC3 (HGNC:23639): (SKI3 subunit of superkiller complex) This gene encodes a protein with twenty tetratricopeptide (TPR) repeats. Tetratricopeptide repeat containing motifs are found in a variety of proteins and may mediate protein-protein interactions and chaperone activity. Mutations in this gene are associated with trichohepatoenteric syndrome. [provided by RefSeq, Jul 2010]

SKIC3 Gene-Disease associations (from GenCC):

• trichohepatoenteric syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• trichohepatoenteric syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13214204).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014639.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIC3	NM_014639.4	MANE Select	c.4655C>G	p.Thr1552Arg	missense	Exon 43 of 43	NP_055454.1	Q6PGP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIC3	ENST00000358746.7	TSL:1 MANE Select	c.4655C>G	p.Thr1552Arg	missense	Exon 43 of 43	ENSP00000351596.3	Q6PGP7
	SKIC3	ENST00000969289.1		c.4712C>G	p.Thr1571Arg	missense	Exon 43 of 43	ENSP00000639348.1
	SKIC3	ENST00000698479.1		c.4697C>G	p.Thr1566Arg	missense	Exon 44 of 44	ENSP00000513748.1	A0A8V8TMA8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.70
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Benign	0.42	T
Polyphen		0.059	B
Vest4		0.23
MutPred		0.17		Gain of MoRF binding (P = 0.0229)
MVP		0.72
MPC		0.091
ClinPred		0.14	T
GERP RS		0.067
Varity_R		0.070
gMVP		0.48
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

hg19: chr5-94800351;