rs1334099693

Positions:

• chr6-21594732-C-A
• chr6-21594732-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003107.3(SOX4):​c.198C>A​(p.Phe66Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOX4 NM_003107.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.02

Genes affected

SOX4 (HGNC:11200): (SRY-box transcription factor 4) This intronless 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, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a DNA_binding_region HMG box (size 68) in uniprot entity SOX4_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_003107.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 6-21594732-C-A is Pathogenic according to our data. Variant chr6-21594732-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548142.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-21594732-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX4	NM_003107.3	c.198C>A	p.Phe66Leu	missense_variant	1/1	ENST00000244745.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX4	ENST00000244745.4	c.198C>A	p.Phe66Leu	missense_variant	1/1		NM_003107.3	P1
	ENST00000637901.1	n.168+694G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443688 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716158

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, mild Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

Feb 20, 2019

The p.Phe66Leu variant is de novo, it is absent in population databases and it involves a higly conserved residue in the HMG box DNA-binding domain of the protein. Three further patients were identified with de novo missense variants affecting the HMG box DNA-binding domain of SOX4. Intellectual disability and similar facial dysmorphisms were present in all four. Functional assays demonstrated that SOX4 proteins carrying these four variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. -

Coffin-Siris syndrome 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 02, 2023

- -

Developmental delay;C3714756:Intellectual disability;na:Mild facial and digital morphological abnormalities Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.90
Sift	Benign	0.032	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.82		Loss of helix (P = 0.0376);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.78
gMVP		1.0

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: rs1334099693; hg19: chr6-21594963;