rs267607083

Positions:

• chr8-54459525-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022454.4(SOX17):​c.775T>A​(p.Tyr259Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,529,242 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (18 hom.)
• Consequence: SOX17 NM_022454.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 1.74

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069889724).
• BP6: Variant 8-54459525-T-A is Benign according to our data. Variant chr8-54459525-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 18413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 387 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX17	NM_022454.4	c.775T>A	p.Tyr259Asn	missense_variant	2/2	ENST00000297316.5	NP_071899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX17	ENST00000297316.5	c.775T>A	p.Tyr259Asn	missense_variant	2/2	1	NM_022454.4	ENSP00000297316.4

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152194 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00660

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00380 AC: 467 AN: 122834 Hom.: 4 AF XY: 0.00403 AC XY: 272 AN XY: 67536

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00809

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00232 AC: 3192 AN: 1376940 Hom.: 18 Cov.: 31 AF XY: 0.00252 AC XY: 1713 AN XY: 679150

Gnomad4 AFR exome AF: 0.000326

Gnomad4 AMR exome AF: 0.00415

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00684

Gnomad4 FIN exome AF: 0.000149

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74472

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00253

ExAC AF: 0.00147 AC: 118

Asia WGS AF: 0.00290 AC: 11 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SOX17: BS2 -

Vesicoureteral reflux 3 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

SOX17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.065	T
Sift4G	Benign	0.15	T
Polyphen		0.95	P
Vest4		0.77
MVP		0.68
MPC		2.4
ClinPred		0.058	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.48

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: rs267607083; hg19: chr8-55372085; COSMIC: COSV52025292;