rs752876296

Variant names:

• chr5-95464645-T-C
• rs752876296
• NM_014639.4:c.4657A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-95464645-T-C
• chr5-95464645-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014639.4(SKIC3):​c.4657A>G​(p.Arg1553Gly) 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 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1553R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SKIC3 NM_014639.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

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.4657A>G	p.Arg1553Gly	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.4657A>G	p.Arg1553Gly	missense	Exon 43 of 43	ENSP00000351596.3	Q6PGP7
	SKIC3	ENST00000969289.1		c.4714A>G	p.Arg1572Gly	missense	Exon 43 of 43	ENSP00000639348.1
	SKIC3	ENST00000698479.1		c.4699A>G	p.Arg1567Gly	missense	Exon 44 of 44	ENSP00000513748.1	A0A8V8TMA8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461336 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726944

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.75		Gain of disorder (P = 0.1379)
MVP		0.91
MPC		0.49
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.48
gMVP		0.53
Mutation Taster		=75/25	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

dbSNP: rs752876296; hg19: chr5-94800349;