Genetic Variant SOX21:p.Met260Ile (chr13-94711270-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007084.4(SOX21):c.780G>A(p.Met260Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000384 in 1,381,188 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 2 hom. )

Consequence

SOX21
NM_007084.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.69

Variant links:

Genes affected

SOX21 (HGNC:11197): (SRY-box transcription factor 21) SRY-related HMG-box (SOX) genes encode a family of DNA-binding proteins containing a 79-amino acid HMG (high mobility group) domain that shares at least 50% sequence identity with the DNA-binding HMG box of the SRY protein (MIM 480000). SOX proteins are divided into 6 subgroups based on sequence similarity within and outside of the HMG domain. For additional background information on SOX genes, see SOX1 (MIM 602148).[supplied by OMIM, Apr 2004]

SOX21 links:

SOX21-AS1 (HGNC:39807): (SOX21 antisense divergent transcript 1)

SOX21-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01784876).

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX21	NM_007084.4 link	c.780G>A	p.Met260Ile	missense_variant	Exon 1 of 1	ENST00000376945.4	NP_009015.1	Q9Y651

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX21	ENST00000376945.4 link	c.780G>A	p.Met260Ile	missense_variant	Exon 1 of 1	6	NM_007084.4	ENSP00000366144.2		Q9Y651
SOX21-AS1	ENST00000665450.1 link	n.132+7685C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000418

AC:

AN:

43094

Hom.:

AF XY:

0.000394

AC XY:

AN XY:

25370

show subpopulations

Gnomad AFR exome

AF:

0.000698

Gnomad AMR exome

AF:

0.000180

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00324

Gnomad NFE exome

AF:

0.000287

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000367

AC:

451

AN:

1228974

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

234

AN XY:

602048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000798

Gnomad4 AMR exome

AF:

0.0000655

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00292

Gnomad4 NFE exome

AF:

0.000344

Gnomad4 OTH exome

AF:

0.000240

GnomAD4 genome

AF:

0.000526

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00340

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000582

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.780G>A (p.M260I) alteration is located in exon 1 (coding exon 1) of the SOX21 gene. This alteration results from a G to A substitution at nucleotide position 780, causing the methionine (M) at amino acid position 260 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.018

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.38

Sift

Uncertain

0.0060

Sift4G

Benign

0.19

Polyphen

0.058

Vest4

0.34

MutPred

0.31

Gain of catalytic residue at L265 (P = 0.0485);

MVP

0.76

ClinPred

0.079

GERP RS

2.9

Varity_R

0.59

gMVP

0.69

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

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