12-23665471-G-A

Variant names:

• chr12-23665471-G-A
• rs1057518928
• NM_006940.6:c.904C>T

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.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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.01
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• 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 12-23665471-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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX5	ENST00000451604.7	TSL:1 MANE Select	c.904C>T	p.Pro302Ser	missense	Exon 7 of 15	ENSP00000398273.2
	SOX5	ENST00000545921.5	TSL:2	c.874C>T	p.Pro292Ser	missense	Exon 7 of 15	ENSP00000443520.1
	SOX5	ENST00000537393.5	TSL:5	c.799C>T	p.Pro267Ser	missense	Exon 7 of 15	ENSP00000439832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 06, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.55	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.51
Sift	Benign	0.060	T
Sift4G	Benign	0.085	T
Polyphen		0.093	B
Vest4		0.57
MutPred		0.32		Gain of catalytic residue at P302 (P = 0.0037)
MVP		0.58
MPC		0.56
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.29
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057518928; hg19: chr12-23818405;