rs2073391817

Variant names:

• chr16-981940-G-T
• rs2073391817
• NM_014587.5:c.18G>T

Variant summary

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

The NM_014587.5(SOX8):​c.18G>T​(p.Glu6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000317 in 1,260,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: SOX8 NM_014587.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15466115).

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.18G>T	p.Glu6Asp	missense	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.18G>T	p.Glu6Asp	missense	Exon 1 of 3	ENSP00000293894.3	P57073
	SOX8	ENST00000711628.1		c.18G>T	p.Glu6Asp	missense	Exon 1 of 3	ENSP00000518816.1	A0AAA9YHU3
	SOX8	ENST00000711625.1		c.18G>T	p.Glu6Asp	missense	Exon 1 of 3	ENSP00000518813.1	A0AAA9YHN4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000317 AC: 4 AN: 1260056 Hom.: 0 Cov.: 30 AF XY: 0.00000321 AC XY: 2 AN XY: 624006

African (AFR) AF: 0.00 AC: 0 AN: 25450

American (AMR) AF: 0.00 AC: 0 AN: 25726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19994

East Asian (EAS) AF: 0.00 AC: 0 AN: 26060

South Asian (SAS) AF: 0.00 AC: 0 AN: 66760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3404

European-Non Finnish (NFE) AF: 0.00000395 AC: 4 AN: 1012234

Other (OTH) AF: 0.00 AC: 0 AN: 49600

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.35
Sift	Benign	0.093	T
Sift4G	Benign	0.26	T
Polyphen		0.80	P
Vest4		0.061
MutPred		0.075		Loss of glycosylation at P11 (P = 0.2608)
MVP		0.76
MPC		2.2
ClinPred		0.34	T
GERP RS		-0.60
PromoterAI		-0.14	Neutral
Varity_R		0.070
gMVP		0.13
Mutation Taster		=93/7	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: rs2073391817; hg19: chr16-1031940;