1-2228951-C-T

Variant names:

• chr1-2228951-C-T
• rs28384811
• NM_003036.4:c.185C>T
• SKI p.Ala62Val

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003036.4(SKI):​c.185C>T​(p.Ala62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,246,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A62S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3532568).

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.185C>T	p.Ala62Val	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.185C>T	p.Ala62Val	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.185C>T	p.Ala62Val	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1427C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1246460 Hom.: 0 Cov.: 32 AF XY: 0.00000326 AC XY: 2 AN XY: 614410

African (AFR) AF: 0.00 AC: 0 AN: 24576

American (AMR) AF: 0.00 AC: 0 AN: 17130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19904

East Asian (EAS) AF: 0.00 AC: 0 AN: 26160

South Asian (SAS) AF: 0.0000317 AC: 2 AN: 63000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3862

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1010154

Other (OTH) AF: 0.00 AC: 0 AN: 50280

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.28	T
Varity_R		0.033
gMVP		0.43
Mutation Taster		=99/1	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: rs28384811;

hg19: chr1-2160390;