Genetic Variant SALL4:p.Leu215Leu (chr20-51791838-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020436.5(SALL4):c.645C>G(p.Leu215Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,614,128 control chromosomes in the GnomAD database, including 755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 55 hom., cov: 33)

Exomes 𝑓: 0.029 ( 700 hom. )

Consequence

SALL4
NM_020436.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.603

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 20-51791838-G-C is Benign according to our data. Variant chr20-51791838-G-C is described in ClinVar as Benign. ClinVar VariationId is 261265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.603 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0206 (3132/152348) while in subpopulation NFE AF = 0.0334 (2272/68034). AF 95% confidence interval is 0.0323. There are 55 homozygotes in GnomAd4. There are 1507 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3132 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020436.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL4	NM_020436.5	MANE Select	c.645C>G	p.Leu215Leu	synonymous	Exon 2 of 4	NP_065169.1
	SALL4	NM_001318031.2		c.645C>G	p.Leu215Leu	synonymous	Exon 2 of 4	NP_001304960.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SALL4	ENST00000217086.9	TSL:1 MANE Select	c.645C>G	p.Leu215Leu	synonymous	Exon 2 of 4	ENSP00000217086.4
SALL4	ENST00000395997.3	TSL:1	c.645C>G	p.Leu215Leu	synonymous	Exon 2 of 4	ENSP00000379319.3
SALL4	ENST00000371539.7	TSL:1	c.131-2697C>G		intron	N/A	ENSP00000360594.3

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3133

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00499

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0281

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0232

AC:

5832

AN:

250948

AF XY:

0.0243

show subpopulations

Gnomad AFR exome

AF:

0.00427

Gnomad AMR exome

AF:

0.00917

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0206

Gnomad NFE exome

AF:

0.0343

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0286

AC:

41777

AN:

1461780

Hom.:

700

Cov.:

AF XY:

0.0288

AC XY:

20912

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00397

AC:

133

AN:

33480

American (AMR)

AF:

0.00901

AC:

403

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

425

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0281

AC:

2425

AN:

86258

European-Finnish (FIN)

AF:

0.0208

AC:

1110

AN:

53316

Middle Eastern (MID)

AF:

0.0173

AC:

100

AN:

5768

European-Non Finnish (NFE)

AF:

0.0320

AC:

35591

AN:

1112006

Other (OTH)

AF:

0.0263

AC:

1588

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2798

5596

8394

11192

13990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1224

2448

3672

4896

6120

<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:

0.0206

AC:

3132

AN:

152348

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1507

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00498

AC:

207

AN:

41584

American (AMR)

AF:

0.0133

AC:

203

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0282

AC:

136

AN:

4830

European-Finnish (FIN)

AF:

0.0210

AC:

223

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0334

AC:

2272

AN:

68034

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

170

341

511

682

852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0223

Hom.:

Bravo

AF:

0.0181

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0296

EpiControl

AF:

0.0290

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Duane-radial ray syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.64

(source)

DANN

Benign

0.69

PhyloP100

-0.60

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over