rs74315425

chr20-51789010-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_020436.5(SALL4):c.2593C>T(p.Arg865Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SALL4 NM_020436.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.47

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PP5: Variant 20-51789010-G-A is Pathogenic according to our data. Variant chr20-51789010-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL4	NM_020436.5	c.2593C>T	p.Arg865Ter	stop_gained	3/4	ENST00000217086.9
SALL4	NM_001318031.2	c.1282C>T	p.Arg428Ter	stop_gained	3/4
SALL4	XM_047440318.1	c.2287C>T	p.Arg763Ter	stop_gained	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL4	ENST00000217086.9	c.2593C>T	p.Arg865Ter	stop_gained	3/4	1	NM_020436.5	P1
SALL4	ENST00000395997.3	c.1282C>T	p.Arg428Ter	stop_gained	3/4	1
SALL4	ENST00000371539.7	c.262C>T	p.Arg88Ter	stop_gained	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duane-radial ray syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg865*) in the SALL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SALL4 are known to be pathogenic (PMID: 15342710, 16086360). This premature translational stop signal has been observed in individual(s) with Duane-radial ray syndrome (PMID: 12395297). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3322). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2019

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 843249, 20301547, 12395297, 25525159, 11826030, 12843316) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	45
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98
GERP RS		4.8

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: rs74315425; hg19: chr20-50405549; COSMIC: COSV53850197; COSMIC: COSV53850197;