chr12-23536466-A-T

Variant names:

• chr12-23536466-A-T
• NM_006940.6:c.1975T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006940.6(SOX5):​c.1975T>A​(p.Tyr659Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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:1
• Conservation: PhyloP100: 9.31

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX5	NM_006940.6	c.1975T>A	p.Tyr659Asn	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.1975T>A	p.Tyr659Asn	missense_variant	Exon 14 of 15	1	NM_006940.6	ENSP00000398273.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 08, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	.;.;D;T;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D;.;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.040	D;T;D;T;T;.;T;D
Sift4G	Benign	0.16	T;T;T;T;T;.;T;T
Polyphen		1.0, 0.82, 0.74	.;D;P;.;D;D;P;.
Vest4		0.73
MutPred		0.45		.;.;Gain of disorder (P = 0.0155);.;.;.;.;.;
MVP		0.53
MPC		3.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.94

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: chr12-23689400;