Genetic Variant SOX18:p.Asp81Glu (chr20-64049274-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018419.3(SOX18):c.243C>G(p.Asp81Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,361,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D81D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

SOX18
NM_018419.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.167

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypotrichosis-lymphedema-telangiectasia-renal defect syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
hypotrichosis-lymphedema-telangiectasia syndrome
Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
hypotrichosis-lymphedema-telangiectasia syndrome (grouping)
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SOX18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11366534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX18	NM_018419.3 link	c.243C>G	p.Asp81Glu	missense_variant	Exon 1 of 2	ENST00000340356.9	NP_060889.1	P35713

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX18	ENST00000340356.9 link	c.243C>G	p.Asp81Glu	missense_variant	Exon 1 of 2	1	NM_018419.3	ENSP00000341815.7		P35713

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.35e-7

AC:

AN:

1361320

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677114

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27462

American (AMR)

AF:

0.00

AC:

AN:

37390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22312

East Asian (EAS)

AF:

0.00

AC:

AN:

29584

South Asian (SAS)

AF:

0.00

AC:

AN:

81010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4900

European-Non Finnish (NFE)

AF:

9.47e-7

AC:

AN:

1055780

Other (OTH)

AF:

0.00

AC:

AN:

54264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.14

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.90

PhyloP100

0.17

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.37

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

0.93

Polyphen

0.0010

Vest4

0.071

MutPred

0.24

Loss of MoRF binding (P = 0.2374);

MVP

0.46

ClinPred

0.043

GERP RS

1.3

PromoterAI

0.011

Neutral

(source)

Varity_R

0.063

gMVP

0.43

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over