rs1210062863

Variant names:

• chr20-64048609-C-A
• rs1210062863
• NM_018419.3:c.712G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-64048609-C-A
• chr20-64048609-C-G
• chr20-64048609-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_018419.3(SOX18):​c.712G>T​(p.Glu238*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000909 in 1,100,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: SOX18 NM_018419.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.69
• 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: Likely_pathogenic. The variant received 8 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. Fraction of 0.384 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-64048609-C-A is Pathogenic according to our data. Variant chr20-64048609-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 433539.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX18	NM_018419.3	c.712G>T	p.Glu238*	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.712G>T	p.Glu238*	stop_gained	Exon 2 of 2	1	NM_018419.3	ENSP00000341815.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.09e-7 AC: 1 AN: 1100096 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 522302

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

African (AFR) AF: 0.00 AC: 0 AN: 22364

American (AMR) AF: 0.00 AC: 0 AN: 7946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13974

East Asian (EAS) AF: 0.00 AC: 0 AN: 25128

South Asian (SAS) AF: 0.00 AC: 0 AN: 27340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2950

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 933416

Other (OTH) AF: 0.00 AC: 0 AN: 44198

⚠️ 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.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome Pathogenic:1

Aug 22, 2017

Area of Clinical and Molecular Genetics, Hospital Universitario Vall de Hebron

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the creation of a termination codon instead of a glutamic acid at position 238 of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		6.7
Vest4		0.39
GERP RS		3.8
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1210062863; hg19: chr20-62679962;