rs1553189986

Variant names:

• chr1-2229401-AGCTCAGCGAGCGCAGCGTCCGCGTGTACCACGAGTGCTTCGGCAAGTGTAAGGGGCTGCTGGTGCCCGAGCTCTACAGCAGCCCGAGCGCCGCCTGCATCCAGTGCCTGGACTGCCGCCTCATGTACCCGCCGCACAAGTTCGTGGTGCACTCGCACAAGGCCCTGGAGAACCGGACCTGCCACTGGGGCTTCGACTCGGCCAACTGGCGGGCCTACATCCTGCTGAGCCAGGATTACACGGGCAAGGAGGAGCAGGC-A
• rs1553189986
• NM_003036.4:c.638_895del

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM4 PP3 PP5_Moderate

The NM_003036.4(SKI):​c.638_895del​(p.Leu213_Ala298del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SKI NM_003036.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.63
• Publications: 0 publications found

Genes affected

SKI (HGNC:10896): (SKI proto-oncogene) This gene encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene. It functions as a repressor of TGF-beta signaling, and may play a role in neural tube development and muscle differentiation. [provided by RefSeq, Oct 2009]

SKI Gene-Disease associations (from GenCC):

• Shprintzen-Goldberg syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003036.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-2229401-AGCTCAGCGAGCGCAGCGTCCGCGTGTACCACGAGTGCTTCGGCAAGTGTAAGGGGCTGCTGGTGCCCGAGCTCTACAGCAGCCCGAGCGCCGCCTGCATCCAGTGCCTGGACTGCCGCCTCATGTACCCGCCGCACAAGTTCGTGGTGCACTCGCACAAGGCCCTGGAGAACCGGACCTGCCACTGGGGCTTCGACTCGGCCAACTGGCGGGCCTACATCCTGCTGAGCCAGGATTACACGGGCAAGGAGGAGCAGGC-A is Pathogenic according to our data. Variant chr1-2229401-AGCTCAGCGAGCGCAGCGTCCGCGTGTACCACGAGTGCTTCGGCAAGTGTAAGGGGCTGCTGGTGCCCGAGCTCTACAGCAGCCCGAGCGCCGCCTGCATCCAGTGCCTGGACTGCCGCCTCATGTACCCGCCGCACAAGTTCGTGGTGCACTCGCACAAGGCCCTGGAGAACCGGACCTGCCACTGGGGCTTCGACTCGGCCAACTGGCGGGCCTACATCCTGCTGAGCCAGGATTACACGGGCAAGGAGGAGCAGGC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 463409.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003036.4. 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
	SKI	NM_003036.4	MANE Select	c.638_895del	p.Leu213_Ala298del	disruptive_inframe_deletion	Exon 1 of 7	NP_003027.1	P12755

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	ENST00000378536.5	TSL:1 MANE Select	c.638_895del	p.Leu213_Ala298del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.638_895del	p.Leu213_Ala298del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1880_137+2137del		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Shprintzen-Goldberg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553189986;

hg19: chr1-2160840;