NM_006940.6:c.2270A>G

Variant names:

• chr12-23534241-T-C
• rs546370374
• NM_006940.6:c.2270A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006940.6(SOX5):​c.2270A>G​(p.His757Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SOX5 NM_006940.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12
• Publications: 0 publications found

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]

SOX5 Gene-Disease associations (from GenCC):

• Lamb-Shaffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• developmental and speech delay due to SOX5 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17611593).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006940.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX5	NM_006940.6	MANE Select	c.2270A>G	p.His757Arg	missense	Exon 15 of 15	NP_008871.3
	SOX5	NM_001261415.3		c.2240A>G	p.His747Arg	missense	Exon 15 of 15	NP_001248344.1	P35711-5
	SOX5	NM_152989.5		c.2231A>G	p.His744Arg	missense	Exon 18 of 18	NP_694534.1	T2CYZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX5	ENST00000451604.7	TSL:1 MANE Select	c.2270A>G	p.His757Arg	missense	Exon 15 of 15	ENSP00000398273.2	P35711-1
	SOX5	ENST00000396007.6	TSL:1	c.1112A>G	p.His371Arg	missense	Exon 7 of 7	ENSP00000379328.2	P35711-3
	SOX5	ENST00000900854.1		c.2270A>G	p.His757Arg	missense	Exon 16 of 16	ENSP00000570913.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251352 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.20
Sift	Benign	0.71	T
Sift4G	Benign	0.52	T
Polyphen		0.43	B
Vest4		0.46
MutPred		0.17		Gain of catalytic residue at H757 (P = 0.015)
MVP		0.32
MPC		0.16
ClinPred		0.18	T
GERP RS		6.0
Varity_R		0.18
gMVP		0.12
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs546370374; hg19: chr12-23687175;