12-23534377-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_006940.6(SOX5):c.2134A>G(p.Thr712Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,026 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SOX5 NM_006940.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SOX5
• BP4: Computational evidence support a benign effect (MetaRNN=0.13439888).
• BP6: Variant 12-23534377-T-C is Benign according to our data. Variant chr12-23534377-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3167799.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000197 (3/152156) while in subpopulation EAS AF= 0.000387 (2/5172). AF 95% confidence interval is 0.0000684. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX5	NM_006940.6	c.2134A>G	p.Thr712Ala	missense_variant	15/15	ENST00000451604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX5	ENST00000451604.7	c.2134A>G	p.Thr712Ala	missense_variant	15/15	1	NM_006940.6	A1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251332 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 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: 0.000277

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	0.057
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T;T;T;.;.;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N;N;N;N;.;N;N
REVEL	Benign	0.061
Sift	Benign	0.080	T;T;T;T;T;.;T;T
Sift4G	Benign	0.54	T;T;T;T;T;.;T;T
Polyphen		0.091, 0.38, 0.10	.;B;B;.;B;B;B;.
Vest4		0.048
MutPred		0.24		.;.;Gain of catalytic residue at V715 (P = 0.01);.;.;.;.;.;
MVP		0.18
MPC		0.14
ClinPred		0.090	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.23

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: rs748104544; hg19: chr12-23687311;