20-51790301-C-T

Variant names:

• chr20-51790301-C-T
• rs61737142
• NM_020436.5:c.2182G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020436.5(SALL4):​c.2182G>A​(p.Ala728Thr) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A728P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.630
• Publications: 1 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16106096).

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.2182G>A	p.Ala728Thr	missense	Exon 2 of 4	NP_065169.1
	SALL4	NM_001318031.2		c.1150+1032G>A		intron	N/A	NP_001304960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL4	ENST00000217086.9	TSL:1 MANE Select	c.2182G>A	p.Ala728Thr	missense	Exon 2 of 4	ENSP00000217086.4
	SALL4	ENST00000395997.3	TSL:1	c.1150+1032G>A		intron	N/A	ENSP00000379319.3
	SALL4	ENST00000371539.7	TSL:1	c.131-1160G>A		intron	N/A	ENSP00000360594.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.63
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.054
Sift	Benign	0.17	T
Sift4G	Benign	0.24	T
Polyphen		0.67	P
Vest4		0.18
MutPred		0.22		Gain of helix (P = 0.132)
MVP		0.30
MPC		0.46
ClinPred		0.55	D
GERP RS		3.6
Varity_R		0.057
gMVP		0.20
Mutation Taster		=94/6	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: rs61737142; hg19: chr20-50406840;