chr20-64048360-C-T

Position:

• chr20-64048360-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_018419.3(SOX18):​c.961G>A​(p.Asp321Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000735 in 1,584,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: SOX18 NM_018419.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14662918).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000598 (91/152126) while in subpopulation NFE AF= 0.000972 (66/67932). AF 95% confidence interval is 0.000783. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX18	NM_018419.3	c.961G>A	p.Asp321Asn	missense_variant	2/2	ENST00000340356.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX18	ENST00000340356.9	c.961G>A	p.Asp321Asn	missense_variant	2/2	1	NM_018419.3	P1

Frequencies

GnomAD3 genomes AF: 0.000599 AC: 91 AN: 152012 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000521 AC: 101 AN: 193974 Hom.: 0 AF XY: 0.000498 AC XY: 53 AN XY: 106446

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.000299

Gnomad ASJ exome AF: 0.00167

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000383

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000855

Gnomad OTH exome AF: 0.000397

GnomAD4 exome AF: 0.000749 AC: 1073 AN: 1432560 Hom.: 1 Cov.: 31 AF XY: 0.000702 AC XY: 499 AN XY: 710492

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000884

Gnomad4 OTH exome AF: 0.000473

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40 AN XY: 74370

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000972

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000769 Hom.: 0

Bravo AF: 0.000540

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000473 AC: 4

ExAC AF: 0.000383 AC: 45

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 321 of the SOX18 protein (p.Asp321Asn). This variant is present in population databases (rs200668348, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SOX18-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SOX18 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.76
ClinPred		0.077	T
GERP RS		4.0
Varity_R		0.56
gMVP		0.44

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: rs200668348; hg19: chr20-62679713;