rs41274696

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020436.5(SALL4):c.2215G>T(p.Ala739Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,614,146 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 17 hom. )

Consequence

SALL4
NM_020436.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.32

Publications

9 publications found

Variant links:

Genes affected

SALL4 (HGNC:15924): (spalt like transcription factor 4) This gene encodes a zinc finger transcription factor thought to play a role in the development of abducens motor neurons. Defects in this gene are a cause of Duane-radial ray syndrome (DRRS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

SALL4 Gene-Disease associations (from GenCC):

Duane-radial ray syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
Duane retraction syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
IVIC syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SALL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071076155).

BP6

Variant 20-51790268-C-A is Benign according to our data. Variant chr20-51790268-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 433 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL4	NM_020436.5 link	c.2215G>T	p.Ala739Ser	missense_variant	Exon 2 of 4	ENST00000217086.9	NP_065169.1	Q9UJQ4-1
SALL4	XM_047440318.1 link	c.1909G>T	p.Ala637Ser	missense_variant	Exon 2 of 4		XP_047296274.1
SALL4	NM_001318031.2 link	c.1150+1065G>T		intron_variant	Intron 2 of 3		NP_001304960.1	Q9UJQ4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SALL4	ENST00000217086.9 link	c.2215G>T	p.Ala739Ser	missense_variant	Exon 2 of 4	1	NM_020436.5	ENSP00000217086.4	Q9UJQ4-1
SALL4	ENST00000395997.3 link	c.1150+1065G>T		intron_variant	Intron 2 of 3	1		ENSP00000379319.3	Q9UJQ4-2
SALL4	ENST00000371539.7 link	c.131-1127G>T		intron_variant	Intron 1 of 2	1		ENSP00000360594.3	Q6Y8G5

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

434

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00547

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00450

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00264

AC:

663

AN:

251324

AF XY:

0.00274

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00485

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00389

AC:

5689

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

2801

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00101

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00304

AC:

262

AN:

86256

European-Finnish (FIN)

AF:

0.00459

AC:

245

AN:

53408

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00443

AC:

4922

AN:

1112010

Other (OTH)

AF:

0.00283

AC:

171

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

405

810

1215

1620

2025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00284

AC:

433

AN:

152272

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

201

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41556

American (AMR)

AF:

0.00170

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00228

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00547

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00450

AC:

306

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00321

Hom.:

Bravo

AF:

0.00228

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00245

AC:

298

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 13, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SALL4: BP4, BS2 -

not specified

Benign:1

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Duane-radial ray syndrome

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SALL4-related disorder

Benign:1

Jul 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.52

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.10

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.46

M_CAP

Benign

0.0029

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

PhyloP100

1.3

PrimateAI

Benign

0.26

PROVEAN

Benign

1.0

REVEL

Benign

0.033

Sift

Benign

0.86

Sift4G

Benign

0.90

Polyphen

0.0010

Vest4

0.017

MVP

0.24

MPC

0.30

ClinPred

0.0040

GERP RS

-0.14

Varity_R

0.036

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over