NM_003036.4:c.15A>C

Variant names:

• chr1-2228781-A-C
• rs1202073334
• NM_003036.4:c.15A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003036.4(SKI):​c.15A>C​(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000875 in 1,142,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP7: Synonymous conserved (PhyloP=0.195 with no splicing effect.

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.15A>C	p.Ala5Ala	synonymous	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.15A>C	p.Ala5Ala	synonymous	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.15A>C	p.Ala5Ala	synonymous	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1257A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.75e-7 AC: 1 AN: 1142988 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 560632

⚠️ 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: 23166

American (AMR) AF: 0.00 AC: 0 AN: 21346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17402

East Asian (EAS) AF: 0.00 AC: 0 AN: 19136

South Asian (SAS) AF: 0.00 AC: 0 AN: 55248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3038

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 938508

Other (OTH) AF: 0.00 AC: 0 AN: 43154

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	11
DANN	Benign	0.33
PhyloP100		0.20
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.4
Mutation Taster		=100/0	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: rs1202073334; hg19: chr1-2160220;