chr1-2306752-A-C

Position:

• chr1-2306752-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003036.4(SKI):​c.2174A>C​(p.Glu725Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,522,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.210

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048023462).
• BP6: Variant 1-2306752-A-C is Benign according to our data. Variant chr1-2306752-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.2174A>C	p.Glu725Ala	missense_variant	7/7	ENST00000378536.5	NP_003027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.2174A>C	p.Glu725Ala	missense_variant	7/7	1	NM_003036.4	ENSP00000367797	P1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152000 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 30 AN: 1370082 Hom.: 0 Cov.: 32 AF XY: 0.0000222 AC XY: 15 AN XY: 675516

Gnomad4 AFR exome AF: 0.000769

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: 9.34e-7

Gnomad4 OTH exome AF: 0.000123

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74344

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.0000528 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2018

The p.E725A variant (also known as c.2174A>C), located in coding exon 7 of the SKI gene, results from an A to C substitution at nucleotide position 2174. The glutamic acid at codon 725 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2019

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 213700; Landrum et al., 2016) -

Shprintzen-Goldberg syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.048	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.35
Sift	Benign	0.044	D
Sift4G	Benign	0.39	T
Polyphen		0.075	B
Vest4		0.19
MutPred		0.20		Loss of solvent accessibility (P = 0.0769);
MVP		0.64
MPC		1.2
ClinPred		0.18	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.059
gMVP		0.18

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: rs747798210; hg19: chr1-2238191;