rs1135401816

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SOX5 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 3.1513 (above the threshold of 3.09). Trascript score misZ: 3.799 (above the threshold of 3.09). GenCC associations: The gene is linked to Lamb-Shaffer syndrome, developmental and speech delay due to SOX5 deficiency.
• 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 id is 431148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX5	NM_006940.6	c.1895C>A	p.Thr632Asn	missense_variant	Exon 14 of 15	ENST00000451604.7	NP_008871.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX5	ENST00000451604.7	c.1895C>A	p.Thr632Asn	missense_variant	Exon 14 of 15	1	NM_006940.6	ENSP00000398273.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lamb-Shaffer syndrome Pathogenic:1

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

autism with no language; tall stature; macrocephaly -

Intellectual disability Uncertain:1

Aug 05, 2019

Institute for Human Genetics, University Hospital Essen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;.;D;T;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.9	.;.;M;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D
Polyphen		0.99, 1.0, 1.0	.;D;D;.;D;D;D;.
Vest4		0.61
MutPred		0.33		.;.;Gain of catalytic residue at P627 (P = 0);.;.;.;.;.;
MVP		0.73
MPC		3.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs1135401816; hg19: chr12-23689480;