rs74315430

Variant names:

• chr20-64048601-G-T
• rs74315430
• NM_018419.3:c.720C>A

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.720C>A​(p.Cys240*) 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: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.89
• Publications: 2 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 0.377 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-64048601-G-T is Pathogenic according to our data. Variant chr20-64048601-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 8002.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018419.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX18	NM_018419.3	MANE Select	c.720C>A	p.Cys240*	stop_gained	Exon 2 of 2	NP_060889.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX18	ENST00000340356.9	TSL:1 MANE Select	c.720C>A	p.Cys240*	stop_gained	Exon 2 of 2	ENSP00000341815.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1090034 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 516426

African (AFR) AF: 0.00 AC: 0 AN: 22270

American (AMR) AF: 0.00 AC: 0 AN: 7876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13694

East Asian (EAS) AF: 0.00 AC: 0 AN: 25012

South Asian (SAS) AF: 0.00 AC: 0 AN: 24884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 927544

Other (OTH) AF: 0.00 AC: 0 AN: 43686

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		1.9
Vest4		0.70
GERP RS		2.8
Mutation Taster		=4/196	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: rs74315430; hg19: chr20-62679954;