rs74315429

Variant names:

• chr20-51788940-T-C
• rs74315429
• NM_020436.5:c.2663A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_020436.5(SALL4):​c.2663A>G​(p.His888Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. H888H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.02
• Publications: 10 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 20-51788940-T-C is Pathogenic according to our data. Variant chr20-51788940-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3329.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL4	NM_020436.5	c.2663A>G	p.His888Arg	missense_variant	Exon 3 of 4	ENST00000217086.9	NP_065169.1
SALL4	NM_001318031.2	c.1352A>G	p.His451Arg	missense_variant	Exon 3 of 4		NP_001304960.1
SALL4	XM_047440318.1	c.2357A>G	p.His786Arg	missense_variant	Exon 3 of 4		XP_047296274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SALL4	ENST00000217086.9	c.2663A>G	p.His888Arg	missense_variant	Exon 3 of 4	1	NM_020436.5	ENSP00000217086.4
SALL4	ENST00000395997.3	c.1352A>G	p.His451Arg	missense_variant	Exon 3 of 4	1		ENSP00000379319.3
SALL4	ENST00000371539.7	c.332A>G	p.His111Arg	missense_variant	Exon 2 of 3	1		ENSP00000360594.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Duane-radial ray syndrome Pathogenic:1 Other:1

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.4	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.92		Gain of MoRF binding (P = 0.0334);.;.;
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs74315429; hg19: chr20-50405479;