rs794728015

Positions:

• chr20-64048840-G-A
• chr20-64048840-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000340356.9(SOX18):​c.481C>T​(p.Gln161Ter) 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 ENST00000340356.9 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.45

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 4 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/exons	MANE	Protein	UniProt
SOX18	NM_018419.3	c.481C>T	p.Gln161Ter	stop_gained	2/2	ENST00000340356.9	NP_060889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX18	ENST00000340356.9	c.481C>T	p.Gln161Ter	stop_gained	2/2	1	NM_018419.3	ENSP00000341815	P1

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

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Pathogenic, criteria provided, single submitter	research	Andelfinger Lab, Centre de Recherche, CHU Sainte Justine	Oct 01, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 14, 2018	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2023

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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 162093). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SOX18 function (PMID: 31358114). 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. -

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
MutationTaster	Benign	1.0	D
Vest4		0.67
GERP RS		3.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728015; hg19: chr20-62680193;