20-51791943-A-G

Variant names:

• chr20-51791943-A-G
• rs6013281
• NM_020436.5:c.540T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020436.5(SALL4):​c.540T>C​(p.Asn180Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,230 control chromosomes in the GnomAD database, including 800,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75670 hom., cov: 34)
  • Exomes 𝑓: 1.0 (724433 hom.)
• Consequence: SALL4 NM_020436.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.406
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-51791943-A-G is Benign according to our data. Variant chr20-51791943-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.406 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 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.540T>C	p.Asn180Asn	synonymous	Exon 2 of 4	NP_065169.1	Q9UJQ4-1
	SALL4	NM_001318031.2		c.540T>C	p.Asn180Asn	synonymous	Exon 2 of 4	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.540T>C	p.Asn180Asn	synonymous	Exon 2 of 4	ENSP00000217086.4	Q9UJQ4-1
	SALL4	ENST00000395997.3	TSL:1	c.540T>C	p.Asn180Asn	synonymous	Exon 2 of 4	ENSP00000379319.3	Q9UJQ4-2
	SALL4	ENST00000371539.7	TSL:1	c.131-2802T>C		intron	N/A	ENSP00000360594.3	Q6Y8G5

Frequencies

GnomAD3 genomes AF: 0.997 AC: 151717 AN: 152220 Hom.: 75610 Cov.: 34

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.995

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.995

Gnomad OTH AF: 0.996

GnomAD2 exomes AF: 0.997 AC: 250539 AN: 251400 AF XY: 0.996

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.995

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.996 AC: 1455361 AN: 1461892 Hom.: 724433 Cov.: 93 AF XY: 0.995 AC XY: 723929 AN XY: 727246

African (AFR) AF: 0.997 AC: 33391 AN: 33480

American (AMR) AF: 0.999 AC: 44686 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 25970 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 0.995 AC: 85831 AN: 86258

European-Finnish (FIN) AF: 0.999 AC: 53344 AN: 53418

Middle Eastern (MID) AF: 0.993 AC: 5727 AN: 5768

European-Non Finnish (NFE) AF: 0.995 AC: 1106537 AN: 1112012

Other (OTH) AF: 0.996 AC: 60177 AN: 60396

GnomAD4 genome AF: 0.997 AC: 151836 AN: 152338 Hom.: 75670 Cov.: 34 AF XY: 0.997 AC XY: 74268 AN XY: 74484

African (AFR) AF: 0.998 AC: 41491 AN: 41586

American (AMR) AF: 0.999 AC: 15298 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 3452 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5148 AN: 5148

South Asian (SAS) AF: 0.995 AC: 4808 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10627 AN: 10632

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.995 AC: 67709 AN: 68042

Other (OTH) AF: 0.996 AC: 2105 AN: 2114

Alfa AF: 0.995 Hom.: 31250

Bravo AF: 0.997

Asia WGS AF: 0.999 AC: 3473 AN: 3478

EpiCase AF: 0.995

EpiControl AF: 0.996

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Duane-radial ray syndrome (2)
-	-	2	not provided (2)
-	-	1	Oculootoradial syndrome (1)
-	-	1	Oculootoradial syndrome;C1623209:Duane-radial ray syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.46
DANN	Benign	0.42
PhyloP100		-0.41
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: rs6013281; hg19: chr20-50408482; COSMIC: COSV108040003; COSMIC: COSV108040003;