chr20-51790963-A-C

Variant names:

• chr20-51790963-A-C
• rs6126344
• NM_020436.5:c.1520T>G

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.1520T>G​(p.Leu507Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,613,936 control chromosomes in the GnomAD database, including 99,606 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L507L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7711 hom., cov: 31)
  • Exomes 𝑓: 0.35 (91895 hom.)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.27
• Publications: 37 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=5.705168E-5).
• BP6: Variant 20-51790963-A-C is Benign according to our data. Variant chr20-51790963-A-C is described in ClinVar as Benign. ClinVar VariationId is 261259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 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.1520T>G	p.Leu507Arg	missense	Exon 2 of 4	NP_065169.1	Q9UJQ4-1
	SALL4	NM_001318031.2		c.1150+370T>G		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.1520T>G	p.Leu507Arg	missense	Exon 2 of 4	ENSP00000217086.4	Q9UJQ4-1
	SALL4	ENST00000395997.3	TSL:1	c.1150+370T>G		intron	N/A	ENSP00000379319.3	Q9UJQ4-2
	SALL4	ENST00000371539.7	TSL:1	c.131-1822T>G		intron	N/A	ENSP00000360594.3	Q6Y8G5

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45679 AN: 151968 Hom.: 7726 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.351 AC: 88212 AN: 251198 AF XY: 0.359

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.598

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.350 AC: 511789 AN: 1461848 Hom.: 91895 Cov.: 73 AF XY: 0.353 AC XY: 256596 AN XY: 727220

African (AFR) AF: 0.137 AC: 4600 AN: 33480

American (AMR) AF: 0.291 AC: 12997 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10803 AN: 26134

East Asian (EAS) AF: 0.546 AC: 21662 AN: 39700

South Asian (SAS) AF: 0.406 AC: 35019 AN: 86258

European-Finnish (FIN) AF: 0.321 AC: 17131 AN: 53392

Middle Eastern (MID) AF: 0.340 AC: 1961 AN: 5768

European-Non Finnish (NFE) AF: 0.347 AC: 386079 AN: 1111998

Other (OTH) AF: 0.357 AC: 21537 AN: 60394

GnomAD4 genome AF: 0.300 AC: 45670 AN: 152088 Hom.: 7711 Cov.: 31 AF XY: 0.303 AC XY: 22536 AN XY: 74344

African (AFR) AF: 0.147 AC: 6092 AN: 41518

American (AMR) AF: 0.339 AC: 5174 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1475 AN: 3472

East Asian (EAS) AF: 0.581 AC: 2990 AN: 5148

South Asian (SAS) AF: 0.431 AC: 2077 AN: 4822

European-Finnish (FIN) AF: 0.317 AC: 3357 AN: 10584

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23330 AN: 67966

Other (OTH) AF: 0.359 AC: 756 AN: 2106

Alfa AF: 0.334 Hom.: 25253

Bravo AF: 0.298

TwinsUK AF: 0.362 AC: 1344

ALSPAC AF: 0.365 AC: 1407

ESP6500AA AF: 0.150 AC: 660

ESP6500EA AF: 0.344 AC: 2957

ExAC AF: 0.350 AC: 42537

Asia WGS AF: 0.497 AC: 1727 AN: 3478

EpiCase AF: 0.356

EpiControl AF: 0.361

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Duane-radial ray syndrome (3)
-	-	2	not provided (2)
-	-	1	Oculootoradial syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.000057	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.059
Sift	Benign	0.59	T
Sift4G	Benign	0.47	T
Polyphen		0.024	B
Vest4		0.24
MPC		1.0
ClinPred		0.0043	T
GERP RS		1.9
Varity_R		0.068
gMVP		0.56
Mutation Taster		=95/5	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: rs6126344; hg19: chr20-50407502; COSMIC: COSV53850292; COSMIC: COSV53850292;