16-982011-C-A

Variant names:

• chr16-982011-C-A
• rs866281747
• NM_014587.5:c.89C>A

Variant summary

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

The NM_014587.5(SOX8):​c.89C>A​(p.Ser30*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000794 in 1,260,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: SOX8 NM_014587.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 1 publications found

Genes affected

SOX8 (HGNC:11203): (SRY-box transcription factor 8) 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 activator after forming a protein complex with other proteins. This protein may be involved in brain development and function. Haploinsufficiency for this protein may contribute to the cognitive disability found in an alpha-thalassemia-related syndrome (ART-16). This protein is also highly expressed in the majority of human hepatocellular carcinomas and promotes cellular proliferation and enhanced tumor growth. [provided by RefSeq, Jul 2017]

SOX8 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014587.5. 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
	SOX8	NM_014587.5	MANE Select	c.89C>A	p.Ser30*	stop_gained	Exon 1 of 3	NP_055402.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX8	ENST00000293894.4	TSL:1 MANE Select	c.89C>A	p.Ser30*	stop_gained	Exon 1 of 3	ENSP00000293894.3	P57073
	SOX8	ENST00000711628.1		c.89C>A	p.Ser30*	stop_gained	Exon 1 of 3	ENSP00000518816.1	A0AAA9YHU3
	SOX8	ENST00000711625.1		c.89C>A	p.Ser30*	stop_gained	Exon 1 of 3	ENSP00000518813.1	A0AAA9YHN4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000101 AC: 1 AN: 98558 AF XY: 0.0000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000414

GnomAD4 exome AF: 7.94e-7 AC: 1 AN: 1260024 Hom.: 0 Cov.: 30 AF XY: 0.00000160 AC XY: 1 AN XY: 623392

⚠️ 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: 25768

American (AMR) AF: 0.00 AC: 0 AN: 25284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20402

East Asian (EAS) AF: 0.00 AC: 0 AN: 26922

South Asian (SAS) AF: 0.00 AC: 0 AN: 63338

European-Finnish (FIN) AF: 0.0000328 AC: 1 AN: 30490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3434

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1014290

Other (OTH) AF: 0.00 AC: 0 AN: 50096

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	0.98
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		3.6
Vest4		0.45
GERP RS		3.0
PromoterAI		0.013	Neutral

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: rs866281747; hg19: chr16-1032011;