20-51791943-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020436.5(SALL4):​c.540T>A​(p.Asn180Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N180N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

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>A	p.Asn180Lys	missense	Exon 2 of 4	NP_065169.1	Q9UJQ4-1
	SALL4	NM_001318031.2		c.540T>A	p.Asn180Lys	missense	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>A	p.Asn180Lys	missense	Exon 2 of 4	ENSP00000217086.4	Q9UJQ4-1
	SALL4	ENST00000395997.3	TSL:1	c.540T>A	p.Asn180Lys	missense	Exon 2 of 4	ENSP00000379319.3	Q9UJQ4-2
	SALL4	ENST00000371539.7	TSL:1	c.131-2802T>A		intron	N/A	ENSP00000360594.3	Q6Y8G5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 93

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.41
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.54		Gain of MoRF binding (P = 0.0355)
MVP		0.84
MPC		1.2
ClinPred		1.0	D
GERP RS		-5.0
Varity_R		0.80
gMVP		0.28
Mutation Taster		=72/28	polymorphism

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;