12-23536546-G-T

Variant names:

• chr12-23536546-G-T
• rs1135401816
• NM_006940.6:c.1895C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.98
• Publications: 3 publications found

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

ACMG classification

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

Sel.	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

Sel.	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.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability (1)
1	-	-	Lamb-Shaffer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
PhyloP100		10
Varity_R		0.81
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1135401816; hg19: chr12-23689480;