Variant 20-64048216-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018419.3(SOX18):c.1105C>G(p.Leu369Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SOX18
NM_018419.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.43

Variant links:

Genes affected

SOX18 (HGNC:11194): (SRY-box transcription factor 18) This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. This protein plays a role in hair, blood vessel, and lymphatic vessel development. Mutations in this gene have been associated with recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. [provided by RefSeq, Jul 2008]

SOX18 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX18	NM_018419.3 linkuse as main transcript	c.1105C>G	p.Leu369Val	missense_variant	2/2	ENST00000340356.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX18	ENST00000340356.9 linkuse as main transcript	c.1105C>G	p.Leu369Val	missense_variant	2/2	1	NM_018419.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000520

AC:

AN:

192444

Hom.:

AF XY:

0.00000947

AC XY:

AN XY:

105650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000338

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1429460

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000247

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Feb 01, 2022

Some in silico tools predict that the p.Leu369Val change is damaging, while others predict this change is tolerated. This variant is located in the C-terminal domain of the protein that has yet to be fully characterized (PMID: 29307792). The p.Leu396Val variant has been observed once in the general population (gnomAD v2.1.1, 1/192,444 alleles) and is absent from the medical literature and patient databases. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.21

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.45

Sift

Uncertain

0.029

Sift4G

Benign

0.31

Polyphen

1.0

Vest4

0.48

MutPred

0.41

Loss of helix (P = 0.0558);

MVP

0.70

ClinPred

0.82

GERP RS

4.0

Varity_R

0.15

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over