rs755766750

Variant names:

• chr12-23534367-A-C
• rs755766750
• NM_006940.6:c.2144T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-23534367-A-C
• chr12-23534367-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006940.6(SOX5):​c.2144T>G​(p.Val715Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX5 NM_006940.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.47
• Publications: 1 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, 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1464147).

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.2144T>G	p.Val715Gly	missense	Exon 15 of 15	NP_008871.3
	SOX5	NM_001261415.3		c.2114T>G	p.Val705Gly	missense	Exon 15 of 15	NP_001248344.1	P35711-5
	SOX5	NM_152989.5		c.2105T>G	p.Val702Gly	missense	Exon 18 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.2144T>G	p.Val715Gly	missense	Exon 15 of 15	ENSP00000398273.2	P35711-1
	SOX5	ENST00000396007.6	TSL:1	c.986T>G	p.Val329Gly	missense	Exon 7 of 7	ENSP00000379328.2	P35711-3
	SOX5	ENST00000900854.1		c.2144T>G	p.Val715Gly	missense	Exon 16 of 16	ENSP00000570913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	SOX5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	N
PhyloP100		2.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.029
Sift	Benign	0.038	D
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.31		Gain of catalytic residue at Y713 (P = 0.001)
MVP		0.068
MPC		0.16
ClinPred		0.25	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.28
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs755766750; hg19: chr12-23687301;