1-2228995-C-T

Variant names:

• chr1-2228995-C-T
• rs1370601989
• NM_003036.4:c.229C>T
• SKI p.Pro77Ser

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003036.4(SKI):​c.229C>T​(p.Pro77Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P77P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 3.88
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.229C>T	p.Pro77Ser	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.229C>T	p.Pro77Ser	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.229C>T	p.Pro77Ser	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1471C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402292 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 694518

African (AFR) AF: 0.00 AC: 0 AN: 32056

American (AMR) AF: 0.00 AC: 0 AN: 37848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.00 AC: 0 AN: 36446

South Asian (SAS) AF: 0.00 AC: 0 AN: 81310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089134

Other (OTH) AF: 0.00 AC: 0 AN: 58416

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Shprintzen-Goldberg syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.037	D
Sift4G	Benign	0.078	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.20
gMVP		0.73
Mutation Taster		=64/36	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

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

Other links and lift over

dbSNP: rs1370601989;

hg19: chr1-2160434;