20-51784443-A-C

Position:

• chr20-51784443-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020436.5(SALL4):​c.2984T>G​(p.Val995Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25409296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL4	NM_020436.5	c.2984T>G	p.Val995Gly	missense_variant	4/4	ENST00000217086.9	NP_065169.1
SALL4	NM_001318031.2	c.1673T>G	p.Val558Gly	missense_variant	4/4		NP_001304960.1
SALL4	XM_047440318.1	c.2678T>G	p.Val893Gly	missense_variant	4/4		XP_047296274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL4	ENST00000217086.9	c.2984T>G	p.Val995Gly	missense_variant	4/4	1	NM_020436.5	ENSP00000217086.4
SALL4	ENST00000395997.3	c.1673T>G	p.Val558Gly	missense_variant	4/4	1		ENSP00000379319.3
SALL4	ENST00000371539.7	c.653T>G	p.Val218Gly	missense_variant	3/3	1		ENSP00000360594.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duane-radial ray syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 25, 2021

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SALL4-related conditions. This sequence change replaces valine with glycine at codon 995 of the SALL4 protein (p.Val995Gly). The valine residue is weakly conserved and there is a moderate physicochemical difference between valine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.31	B;B;.
Vest4		0.17
MutPred		0.62		Loss of stability (P = 0.0145);.;.;
MVP		0.38
MPC		0.63
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.39
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs1601162110; hg19: chr20-50400982; COSMIC: COSV53849884;