chr1-2303376-A-C

Position:

• chr1-2303376-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003036.4(SKI):​c.1187A>C​(p.His396Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.1187A>C	p.His396Pro	missense_variant	3/7	ENST00000378536.5	NP_003027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.1187A>C	p.His396Pro	missense_variant	3/7	1	NM_003036.4	ENSP00000367797	P1
SKI	ENST00000478223.2	n.294A>C		non_coding_transcript_exon_variant	3/3	3
SKI	ENST00000704337.1	n.355A>C		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250622 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135580

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460788 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726728

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.90	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.66
Sift	Benign	0.085	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.76
MutPred		0.36		Gain of glycosylation at H396 (P = 0.0103);
MVP		0.73
MPC		0.87
ClinPred		0.57	D
GERP RS		2.6
Varity_R		0.22
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs987527805; hg19: chr1-2234815;