Genetic Variant SOX18:p.Gln161Lys (chr20-64048840-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018419.3(SOX18):c.481C>A(p.Gln161Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,886 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.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SOX18
NM_018419.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.45

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39872098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX18	NM_018419.3 link	c.481C>A	p.Gln161Lys	missense_variant	Exon 2 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.481C>A	p.Gln161Lys	missense_variant	Exon 2 of 2	1	NM_018419.3	ENSP00000341815.7		P35713

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.00e-7

AC:

AN:

1428198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30962

American (AMR)

AF:

0.00

AC:

AN:

42980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

37358

South Asian (SAS)

AF:

0.00

AC:

AN:

83942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102000

Other (OTH)

AF:

0.00

AC:

AN:

59252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151886

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67930

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.40

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.5

PhyloP100

3.4

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.40

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.027

Polyphen

0.26

Vest4

0.36

MutPred

0.29

Gain of methylation at Q161 (P = 0.0124);

MVP

0.58

ClinPred

0.96

GERP RS

3.2

Varity_R

0.49

gMVP

0.47

Mutation Taster

=84/16

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