12-23534377-T-G

Variant names:

• chr12-23534377-T-G
• NM_006940.6:c.2134A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006940.6(SOX5):​c.2134A>C​(p.Thr712Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOX5 NM_006940.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2983664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX5	NM_006940.6	c.2134A>C	p.Thr712Pro	missense_variant	Exon 15 of 15	ENST00000451604.7	NP_008871.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX5	ENST00000451604.7	c.2134A>C	p.Thr712Pro	missense_variant	Exon 15 of 15	1	NM_006940.6	ENSP00000398273.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;.;T;T;.;.;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;.;D;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.88	.;.;L;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;.;D;D
REVEL	Benign	0.066
Sift	Benign	0.056	T;D;T;D;D;.;D;T
Sift4G	Benign	0.36	T;T;T;T;T;.;T;T
Polyphen		0.0, 0.0040, 0.0010	.;B;B;.;B;B;B;.
Vest4		0.13
MutPred		0.25		.;.;Gain of catalytic residue at Y713 (P = 0.0071);.;.;.;.;.;
MVP		0.15
MPC		0.16
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-23687311;