8-54458346-C-G

Position:

• chr8-54458346-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_022454.4(SOX17):​c.208C>G​(p.Arg70Gly) variant causes a missense 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: 34)
• Consequence: SOX17 NM_022454.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.88

Genes affected

SOX17 (HGNC:18122): (SRY-box transcription factor 17) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 8-54458346-C-G is Pathogenic according to our data. Variant chr8-54458346-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2584495.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX17	NM_022454.4	c.208C>G	p.Arg70Gly	missense_variant	1/2	ENST00000297316.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX17	ENST00000297316.5	c.208C>G	p.Arg70Gly	missense_variant	1/2	1	NM_022454.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sox17- related disorders Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has not been previously reported or functionally characterized in the literature to our knowledge. A different variant at the same amino acid residue (p.Arg70Gln) was previously reported in a mother diagnosed with pulmonary arterial hypertension and atrial septal defect and her son diagnosed with pulmonary arterial hypertension and patent foramen ovale (PMID: 30044643). The c.208C>G (p.Arg70Gly) variant seen in this individual is absent from the gnomAD population database and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this change likely occurred as a de novo event. Based on the available evidence, the c.208C>G (p.Arg70Gly) variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.91		Loss of stability (P = 0.0523);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.96
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-55370906;