rs398124211

Positions:

• chrX-140504323-A-AGCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_005634.3(SOX3):​c.737_738insCGC​(p.Ala247dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000976 in 1,045,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.000068 (0 hom. 22 hem.)
• Consequence: SOX3 NM_005634.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.162

Genes affected

SOX3 (HGNC:11199): (SRY-box transcription factor 3) 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. Mutations in this gene have been associated with X-linked cognitive disability with growth hormone deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005634.3
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX3	NM_005634.3	c.737_738insCGC	p.Ala247dup	inframe_insertion	1/1	ENST00000370536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX3	ENST00000370536.5	c.737_738insCGC	p.Ala247dup	inframe_insertion	1/1		NM_005634.3	P1

Frequencies

GnomAD3 genomes AF: 0.000367 AC: 37 AN: 100807 Hom.: 0 Cov.: 23 AF XY: 0.000280 AC XY: 8 AN XY: 28609

Gnomad AFR AF: 0.0000739

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00629

Gnomad NFE AF: 0.000142

Gnomad OTH AF: 0.000760

GnomAD3 exomes AF: 0.0000284 AC: 1 AN: 35250 Hom.: 0 AF XY: 0.000115 AC XY: 1 AN XY: 8724

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 SAS exome AF: 0.000256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000678 AC: 64 AN: 944350 Hom.: 0 Cov.: 33 AF XY: 0.0000734 AC XY: 22 AN XY: 299620

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000455

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.000128

GnomAD4 genome AF: 0.000377 AC: 38 AN: 100844 Hom.: 0 Cov.: 23 AF XY: 0.000279 AC XY: 8 AN XY: 28650

Gnomad4 AFR AF: 0.0000737

Gnomad4 AMR AF: 0.00276

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000142

Gnomad4 OTH AF: 0.000749

Alfa AF: 0.000490 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -

Autism;C0010417:Cryptorchidism;C0018784:Sensorineural hearing loss disorder;C0036439:Scoliosis;C0038379:Strabismus;C0265677:Hemivertebrae;C0265695:Rib fusion;C0266294:Unilateral renal agenesis;C0392005:Bilateral cleft lip;C0454644:Delayed speech and language development;C0542519:Renal agenesis;C0557874:Global developmental delay;C1301509:Severely reduced visual acuity;C1398522:Bilateral cleft lip and palate;C1849075:Relative macrocephaly;C1860493:Abnormal sternum morphology;C1956257:Pulmonic stenosis;C2981150:Cleft palate;C3553084:Bilateral cleft palate Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

Intellectual disability, X-linked, with panhypopituitarism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

Acute myeloid leukemia;C0030312:Pancytopenia;C0221217:Webbed neck;C0338656:Cognitive impairment;C0349588:Short stature;C0878638:Abnormality of the tongue;C2051831:Pectus excavatum Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

SOX3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124211; hg19: chrX-139586488;