5-95464649-A-T

Variant names:

• chr5-95464649-A-T
• NM_014639.4:c.4653T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014639.4(SKIC3):​c.4653T>A​(p.Asp1551Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar 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: 1.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC3	NM_014639.4	c.4653T>A	p.Asp1551Glu	missense_variant	Exon 43 of 43	ENST00000358746.7	NP_055454.1
SKIC3	XM_047417937.1	c.4653T>A	p.Asp1551Glu	missense_variant	Exon 43 of 43		XP_047273893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC3	ENST00000358746.7	c.4653T>A	p.Asp1551Glu	missense_variant	Exon 43 of 43	1	NM_014639.4	ENSP00000351596.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1551 of the TTC37 protein (p.Asp1551Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TTC37-related conditions. ClinVar contains an entry for this variant (Variation ID: 2117237). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0032	T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	.;N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.74		Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);
MVP		0.86
MPC		0.40
ClinPred		0.98	D
GERP RS		0.66
Varity_R		0.35
gMVP		0.25

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: chr5-94800353;