1-2228866-G-T

Variant names:

• chr1-2228866-G-T
• rs387907306
• NM_003036.4:c.100G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003036.4(SKI):​c.100G>T​(p.Gly34Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000781 in 1,279,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G34V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.60
• Publications: 5 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr1-2228867-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 1-2228866-G-T is Pathogenic according to our data. Variant chr1-2228866-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37262.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.100G>T	p.Gly34Cys	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.100G>T	p.Gly34Cys	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.100G>T	p.Gly34Cys	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1342G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.81e-7 AC: 1 AN: 1279770 Hom.: 0 Cov.: 31 AF XY: 0.00000158 AC XY: 1 AN XY: 632564

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26282

American (AMR) AF: 0.00 AC: 0 AN: 26420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21042

East Asian (EAS) AF: 0.00 AC: 0 AN: 26500

South Asian (SAS) AF: 0.00 AC: 0 AN: 72074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3734

European-Non Finnish (NFE) AF: 9.80e-7 AC: 1 AN: 1020810

Other (OTH) AF: 0.00 AC: 0 AN: 51160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Shprintzen-Goldberg syndrome (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L
PhyloP100		6.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.56		Loss of MoRF binding (P = 0.0852)
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.98
gMVP		0.75
Mutation Taster		=33/67	disease causing (ClinVar)

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: rs387907306; hg19: chr1-2160305;