dbSNP rs1057518928: SOX5:p.Pro302Ser (chr12-23665471-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_006940.6(SOX5):c.904C>T(p.Pro302Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SOX5
NM_006940.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.01

Publications

2 publications found

Variant links:

Genes affected

SOX5 (HGNC:11201): (SRY-box transcription factor 5) 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. The encoded protein may play a role in chondrogenesis. A pseudogene of this gene is located on chromosome 8. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SOX5 Gene-Disease associations (from GenCC):

Lamb-Shaffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
developmental and speech delay due to SOX5 deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SOX5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-23665471-G-A is Pathogenic according to our data. Variant chr12-23665471-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374147.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006940.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOX5	NM_006940.6	MANE Select	c.904C>T	p.Pro302Ser	missense	Exon 7 of 15	NP_008871.3
SOX5	NM_001261415.3		c.874C>T	p.Pro292Ser	missense	Exon 7 of 15	NP_001248344.1
SOX5	NM_152989.5		c.865C>T	p.Pro289Ser	missense	Exon 10 of 18	NP_694534.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOX5	ENST00000451604.7	TSL:1 MANE Select	c.904C>T	p.Pro302Ser	missense	Exon 7 of 15	ENSP00000398273.2
SOX5	ENST00000900854.1		c.904C>T	p.Pro302Ser	missense	Exon 8 of 16	ENSP00000570913.1
SOX5	ENST00000900855.1		c.904C>T	p.Pro302Ser	missense	Exon 8 of 16	ENSP00000570914.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy;C1837397:Severe global developmental delay;C1858120:Generalized hypotonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.088

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

0.55

PhyloP100

8.0

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.51

Sift

Benign

0.060

Sift4G

Benign

0.085

Polyphen

0.093

Vest4

0.57

MutPred

0.32

Gain of catalytic residue at P302 (P = 0.0037)

MVP

0.58

MPC

0.56

ClinPred

0.93

GERP RS

5.3

Varity_R

0.29

gMVP

0.87

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over