20-64049274-G-C

Variant names:

• chr20-64049274-G-C
• rs144785707
• NM_018419.3:c.243C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018419.3(SOX18):​c.243C>G​(p.Asp81Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,361,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D81D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SOX18 NM_018419.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.167
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11366534).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX18	NM_018419.3	MANE Select	c.243C>G	p.Asp81Glu	missense	Exon 1 of 2	NP_060889.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX18	ENST00000340356.9	TSL:1 MANE Select	c.243C>G	p.Asp81Glu	missense	Exon 1 of 2	ENSP00000341815.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1361320 Hom.: 0 Cov.: 34 AF XY: 0.00000148 AC XY: 1 AN XY: 677114

⚠️ 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: 27462

American (AMR) AF: 0.00 AC: 0 AN: 37390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22312

East Asian (EAS) AF: 0.00 AC: 0 AN: 29584

South Asian (SAS) AF: 0.00 AC: 0 AN: 81010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4900

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1055780

Other (OTH) AF: 0.00 AC: 0 AN: 54264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.17
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0010	B
Vest4		0.071
MutPred		0.24		Loss of MoRF binding (P = 0.2374)
MVP		0.46
ClinPred		0.043	T
GERP RS		1.3
PromoterAI		0.011	Neutral
Varity_R		0.063
gMVP		0.43
Mutation Taster		=94/6	polymorphism

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: rs144785707; hg19: chr20-62680627;