12-23534219-T-C

Position:

• chr12-23534219-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP3_Moderate

The NM_006940.6(SOX5):​c.2292A>G​(p.Ter764TrpextTer1) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX5 NM_006940.6 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_006940.6 Downstream stopcodon found after 36 codons.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX5	NM_006940.6	c.2292A>G	p.Ter764TrpextTer1	stop_lost	15/15	ENST00000451604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX5	ENST00000451604.7	c.2292A>G	p.Ter764TrpextTer1	stop_lost	15/15	1	NM_006940.6	A1

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2018

A variant of uncertain significance has been identified in the SOX5 gene. The c.2292 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant changes the normal stop codon to a Tryptophan codon, leading to the addition of one amino acid at the C-terminus. This variant is not observed in large population cohorts (Lek et al., 2016). Other variants that extend the length of the protein have not been previously reported. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.89
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
Vest4		0.43
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555121055; hg19: chr12-23687153;