rs74315429

Positions:

• chr20-51788940-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 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).

• 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

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 Likely_pathogenic. Variant got 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 id is 3329.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL4	ENST00000217086.9	c.2663A>G	p.His888Arg	missense_variant	3/4	1	NM_020436.5	ENSP00000217086	P1
SALL4	ENST00000395997.3	c.1352A>G	p.His451Arg	missense_variant	3/4	1		ENSP00000379319
SALL4	ENST00000371539.7	c.332A>G	p.His111Arg	missense_variant	2/3	1		ENSP00000360594

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -

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;.;.
MutationTaster	Benign	1.0	A;A;A
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

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: rs74315429; hg19: chr20-50405479;