rs6091375

Variant names:

• chr20-51790091-T-G
• rs6091375
• NM_020436.5:c.2392A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020436.5(SALL4):​c.2392A>C​(p.Ile798Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,614,114 control chromosomes in the GnomAD database, including 2,966 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I798V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.077 (636 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2330 hom.)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.895
• Publications: 14 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• Duane retraction syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• IVIC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021042824).
• BP6: Variant 20-51790091-T-G is Benign according to our data. Variant chr20-51790091-T-G is described in ClinVar as Benign. ClinVar VariationId is 261262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL4	NM_020436.5	MANE Select	c.2392A>C	p.Ile798Leu	missense	Exon 2 of 4	NP_065169.1	Q9UJQ4-1
	SALL4	NM_001318031.2		c.1151-950A>C		intron	N/A	NP_001304960.1	Q9UJQ4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL4	ENST00000217086.9	TSL:1 MANE Select	c.2392A>C	p.Ile798Leu	missense	Exon 2 of 4	ENSP00000217086.4	Q9UJQ4-1
	SALL4	ENST00000395997.3	TSL:1	c.1151-950A>C		intron	N/A	ENSP00000379319.3	Q9UJQ4-2
	SALL4	ENST00000371539.7	TSL:1	c.131-950A>C		intron	N/A	ENSP00000360594.3	Q6Y8G5

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11680 AN: 152120 Hom.: 632 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0659

GnomAD2 exomes AF: 0.0476 AC: 11968 AN: 251482 AF XY: 0.0455

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.00179

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0520 AC: 76044 AN: 1461876 Hom.: 2330 Cov.: 31 AF XY: 0.0509 AC XY: 37040 AN XY: 727240

African (AFR) AF: 0.164 AC: 5499 AN: 33480

American (AMR) AF: 0.0338 AC: 1512 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0520 AC: 1358 AN: 26136

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39700

South Asian (SAS) AF: 0.0255 AC: 2197 AN: 86258

European-Finnish (FIN) AF: 0.0274 AC: 1466 AN: 53410

Middle Eastern (MID) AF: 0.0591 AC: 341 AN: 5768

European-Non Finnish (NFE) AF: 0.0541 AC: 60178 AN: 1112004

Other (OTH) AF: 0.0572 AC: 3456 AN: 60396

GnomAD4 genome AF: 0.0769 AC: 11706 AN: 152238 Hom.: 636 Cov.: 32 AF XY: 0.0740 AC XY: 5506 AN XY: 74422

African (AFR) AF: 0.155 AC: 6433 AN: 41524

American (AMR) AF: 0.0470 AC: 718 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4824

European-Finnish (FIN) AF: 0.0278 AC: 295 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0552 AC: 3754 AN: 68018

Other (OTH) AF: 0.0652 AC: 138 AN: 2116

Alfa AF: 0.0619 Hom.: 779

Bravo AF: 0.0820

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.158 AC: 696

ESP6500EA AF: 0.0579 AC: 498

ExAC AF: 0.0510 AC: 6188

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.0586

EpiControl AF: 0.0555

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Duane-radial ray syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.12
DANN	Benign	0.72
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.90
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.018
Sift	Benign	0.67	T
Sift4G	Benign	0.96	T
Polyphen		0.0010	B
Vest4		0.040
MPC		0.33
ClinPred		0.0033	T
GERP RS		-5.1
Varity_R		0.060
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs6091375; hg19: chr20-50406630; COSMIC: COSV107248890; COSMIC: COSV107248890;