chr20-64048840-G-A

Variant names:

• chr20-64048840-G-A
• rs794728015
• NM_018419.3:c.481C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_018419.3(SOX18):​c.481C>T​(p.Gln161*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOX18 NM_018419.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.45
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-64048840-G-A is Pathogenic according to our data. Variant chr20-64048840-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX18	NM_018419.3	c.481C>T	p.Gln161*	stop_gained	Exon 2 of 2	ENST00000340356.9	NP_060889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX18	ENST00000340356.9	c.481C>T	p.Gln161*	stop_gained	Exon 2 of 2	1	NM_018419.3	ENSP00000341815.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1428198 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710636

African (AFR) AF: 0.00 AC: 0 AN: 30962

American (AMR) AF: 0.00 AC: 0 AN: 42980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.00 AC: 0 AN: 37358

South Asian (SAS) AF: 0.00 AC: 0 AN: 83942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102000

Other (OTH) AF: 0.00 AC: 0 AN: 59252

GnomAD4 genome Cov.: 33

Alfa AF: 0.000132 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotrichosis-lymphedema-telangiectasia syndrome Pathogenic:2

Oct 01, 2014

Andelfinger Lab, Centre de Recherche, CHU Sainte Justine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 14, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SOX18 function (PMID: 31358114). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 162093). This premature translational stop signal has been observed in individual(s) with SOX18-related conditions (PMID: 26148450). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln161*) in the SOX18 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 224 amino acid(s) of the SOX18 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.4
Vest4		0.67
GERP RS		3.2
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728015; hg19: chr20-62680193;