chr1-2229115-G-A

Variant names:

• chr1-2229115-G-A
• rs869312901
• NM_003036.4:c.349G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003036.4(SKI):​c.349G>A​(p.Gly117Ser) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G117R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.51
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_003036.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-2229115-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-2229115-G-A is Pathogenic according to our data. Variant chr1-2229115-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1196933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.349G>A	p.Gly117Ser	missense	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.349G>A	p.Gly117Ser	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.349G>A	p.Gly117Ser	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1591G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Intellectual disability (1)
1	-	-	Shprintzen-Goldberg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Loss of ubiquitination at K119 (P = 0.0747)
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		2.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		4.9
Varity_R		0.93
gMVP		0.97
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs869312901; hg19: chr1-2160554;