Genetic Variant NM_006940.6:c.1895C>A (chr12-23536546-G-T) – 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.1895C>A(p.Thr632Asn) 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:1U:1

Conservation

PhyloP100: 9.98

Publications

3 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: G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
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 12-23536546-G-T is Pathogenic according to our data. Variant chr12-23536546-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431148.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	UniProt
SOX5	NM_006940.6	MANE Select	c.1895C>A	p.Thr632Asn	missense	Exon 14 of 15	NP_008871.3
SOX5	NM_001261415.3		c.1865C>A	p.Thr622Asn	missense	Exon 14 of 15	NP_001248344.1	P35711-5
SOX5	NM_152989.5		c.1856C>A	p.Thr619Asn	missense	Exon 17 of 18	NP_694534.1	T2CYZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOX5	ENST00000451604.7	TSL:1 MANE Select	c.1895C>A	p.Thr632Asn	missense	Exon 14 of 15	ENSP00000398273.2	P35711-1
SOX5	ENST00000396007.6	TSL:1	c.737C>A	p.Thr246Asn	missense	Exon 6 of 7	ENSP00000379328.2	P35711-3
SOX5	ENST00000900854.1		c.1895C>A	p.Thr632Asn	missense	Exon 15 of 16	ENSP00000570913.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

Lamb-Shaffer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.67

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.9

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.61

MutPred

0.33

Gain of catalytic residue at P627 (P = 0)

MVP

0.73

MPC

3.0

ClinPred

1.0

GERP RS

5.6

Varity_R

0.81

gMVP

0.90

Mutation Taster

=1/99

disease causing (ClinVar)

(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