Genetic Variant NM_006940.6:c.904C>G (chr12-23665471-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_006940.6(SOX5):c.904C>G(p.Pro302Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P302S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SOX5
NM_006940.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.01

Publications

0 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;

PM5

Other missense variant is known to change same aminoacid residue: 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>G	p.Pro302Ala	missense	Exon 7 of 15	NP_008871.3
SOX5	NM_001261415.3		c.874C>G	p.Pro292Ala	missense	Exon 7 of 15	NP_001248344.1
SOX5	NM_152989.5		c.865C>G	p.Pro289Ala	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>G	p.Pro302Ala	missense	Exon 7 of 15	ENSP00000398273.2
SOX5	ENST00000545921.5	TSL:2	c.874C>G	p.Pro292Ala	missense	Exon 7 of 15	ENSP00000443520.1
SOX5	ENST00000537393.5	TSL:5	c.799C>G	p.Pro267Ala	missense	Exon 7 of 15	ENSP00000439832.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461338

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111604

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.74

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

0.55

PhyloP100

8.0

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.014

Polyphen

0.61

Vest4

0.69

MutPred

0.36

Gain of catalytic residue at P302 (P = 5e-04)

MVP

0.80

MPC

0.76

ClinPred

0.94

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.30

gMVP

0.82

Mutation Taster

=36/64

disease causing

(source)

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

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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