rs41274696

chr20-51790268-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020436.5(SALL4):c.2215G>T(p.Ala739Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,614,146 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (17 hom.)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.32

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071076155).
• BP6: Variant 20-51790268-C-A is Benign according to our data. Variant chr20-51790268-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 195362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-51790268-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 434 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL4	NM_020436.5	c.2215G>T	p.Ala739Ser	missense_variant	2/4	ENST00000217086.9
SALL4	XM_047440318.1	c.1909G>T	p.Ala637Ser	missense_variant	2/4
SALL4	NM_001318031.2	c.1150+1065G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL4	ENST00000217086.9	c.2215G>T	p.Ala739Ser	missense_variant	2/4	1	NM_020436.5	P1
SALL4	ENST00000371539.7	c.131-1127G>T		intron_variant		1
SALL4	ENST00000395997.3	c.1150+1065G>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00264 AC: 663 AN: 251324 Hom.: 2 AF XY: 0.00274 AC XY: 372 AN XY: 135854

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00485

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00389 AC: 5689 AN: 1461874 Hom.: 17 Cov.: 31 AF XY: 0.00385 AC XY: 2801 AN XY: 727240

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00304

Gnomad4 FIN exome AF: 0.00459

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74452

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00343 Hom.: 2

Bravo AF: 0.00228

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00245 AC: 298

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SALL4: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 12, 2014

- -

Duane-radial ray syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

- -

SALL4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.52
Dann	Benign	0.43
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.033
Sift	Benign	0.86	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.017
MVP		0.24
MPC		0.30
ClinPred		0.0040	T
GERP RS		-0.14
Varity_R		0.036
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41274696; hg19: chr20-50406807; COSMIC: COSV53851985; COSMIC: COSV53851985;