6-21594616-C-G

Position:

chr6-21594616-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003107.3(SOX4):c.82C>G(p.Leu28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,608,160 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 87 hom. )

Consequence

SOX4
NM_003107.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.264

Variant links:

Genes affected

SOX4 (HGNC:11200): (SRY-box transcription factor 4) This intronless 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, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein. [provided by RefSeq, Jul 2008]

SOX4 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058346987).

BP6

Variant 6-21594616-C-G is Benign according to our data. Variant chr6-21594616-C-G is described in ClinVar as [Benign]. Clinvar id is 720268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00884 (12863/1455830) while in subpopulation MID AF= 0.0231 (123/5328). AF 95% confidence interval is 0.0198. There are 87 homozygotes in gnomad4_exome. There are 6509 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1277 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX4	NM_003107.3 linkuse as main transcript	c.82C>G	p.Leu28Val	missense_variant	1/1	ENST00000244745.4	NP_003098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX4	ENST00000244745.4 linkuse as main transcript	c.82C>G	p.Leu28Val	missense_variant	1/1		NM_003107.3	ENSP00000244745	P1
	ENST00000637901.1 linkuse as main transcript	n.168+810G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00838

AC:

1276

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00795

AC:

1848

AN:

232390

Hom.:

AF XY:

0.00823

AC XY:

1052

AN XY:

127816

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.00549

Gnomad ASJ exome

AF:

0.00384

Gnomad EAS exome

AF:

0.000116

Gnomad SAS exome

AF:

0.00272

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00878

GnomAD4 exome

AF:

0.00884

AC:

12863

AN:

1455830

Hom.:

Cov.:

AF XY:

0.00899

AC XY:

6509

AN XY:

723968

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00609

Gnomad4 ASJ exome

AF:

0.00457

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00286

Gnomad4 FIN exome

AF:

0.0170

Gnomad4 NFE exome

AF:

0.00962

Gnomad4 OTH exome

AF:

0.00848

GnomAD4 genome

AF:

0.00838

AC:

1277

AN:

152330

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0112

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00740

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.000918

AC:

ESP6500EA

AF:

0.00925

AC:

ExAC

AF:

0.00709

AC:

852

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SOX4: PP3, BS1, BS2 -

SOX4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 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

0.24

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0058

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.39

Sift

Uncertain

0.020

Sift4G

Uncertain

0.041

Polyphen

1.0

Vest4

0.28

MVP

0.98

MPC

1.8

ClinPred

0.026

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.41

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over