rs74315430

Positions:

• chr20-64048601-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000340356.9(SOX18):​c.720C>A​(p.Cys240Ter) 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: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.89

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 Likely_pathogenic. Variant got 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 1 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 id is 8002.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX18	NM_018419.3	c.720C>A	p.Cys240Ter	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.720C>A	p.Cys240Ter	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: 1090034 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 516426

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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 02, 2014

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2023

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26147798, 33851505, 34570228, 29307792, 26148450, 24167460, 12740761, 2484451, 24697860, 30549413, 26631803) -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A
Vest4		0.70
GERP RS		2.8

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

LitVar

Other links and lift over

dbSNP: rs74315430; hg19: chr20-62679954;