1-2306752-A-G

Variant names:

• chr1-2306752-A-G
• rs747798210
• NM_003036.4:c.2174A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_003036.4(SKI):​c.2174A>G​(p.Glu725Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,370,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E725A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.210
• 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: Ambry Genetics, PanelApp Australia, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.262793).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	NM_003036.4	MANE Select	c.2174A>G	p.Glu725Gly	missense	Exon 7 of 7	NP_003027.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	ENST00000378536.5	TSL:1 MANE Select	c.2174A>G	p.Glu725Gly	missense	Exon 7 of 7	ENSP00000367797.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000855 AC: 1 AN: 116978 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 5 AN: 1370084 Hom.: 0 Cov.: 32 AF XY: 0.00000592 AC XY: 4 AN XY: 675516

African (AFR) AF: 0.00 AC: 0 AN: 28604

American (AMR) AF: 0.00 AC: 0 AN: 33750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24260

East Asian (EAS) AF: 0.00 AC: 0 AN: 33536

South Asian (SAS) AF: 0.00 AC: 0 AN: 77042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00000467 AC: 5 AN: 1070118

Other (OTH) AF: 0.00 AC: 0 AN: 56716

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Shprintzen-Goldberg syndrome Uncertain:1

Sep 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SKI protein function. ClinVar contains an entry for this variant (Variation ID: 2142234). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 725 of the SKI protein (p.Glu725Gly).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.21
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.020	D
Sift4G	Benign	0.22	T
Polyphen		0.28	B
Vest4		0.081
MutPred		0.17		Gain of loop (P = 0.0121)
MVP		0.61
MPC		1.3
ClinPred		0.29	T
GERP RS		4.2
Varity_R		0.077
gMVP		0.16
Mutation Taster		=98/2	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: rs747798210; hg19: chr1-2238191;