rs6091375

Positions:

• chr20-51790091-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020436.5(SALL4):​c.2392A>C​(p.Ile798Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,614,114 control chromosomes in the GnomAD database, including 2,966 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (636 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2330 hom.)
• Consequence: SALL4 NM_020436.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.895

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021042824).
• BP6: Variant 20-51790091-T-G is Benign according to our data. Variant chr20-51790091-T-G is described in ClinVar as [Benign]. Clinvar id is 261262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-51790091-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL4	NM_020436.5	c.2392A>C	p.Ile798Leu	missense_variant	2/4	ENST00000217086.9	NP_065169.1
SALL4	XM_047440318.1	c.2086A>C	p.Ile696Leu	missense_variant	2/4		XP_047296274.1
SALL4	NM_001318031.2	c.1151-950A>C		intron_variant			NP_001304960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL4	ENST00000217086.9	c.2392A>C	p.Ile798Leu	missense_variant	2/4	1	NM_020436.5	ENSP00000217086.4
SALL4	ENST00000395997.3	c.1151-950A>C		intron_variant		1		ENSP00000379319.3
SALL4	ENST00000371539.7	c.131-950A>C		intron_variant		1		ENSP00000360594.3

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11680 AN: 152120 Hom.: 632 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0659

GnomAD3 exomes AF: 0.0476 AC: 11968 AN: 251482 Hom.: 476 AF XY: 0.0455 AC XY: 6186 AN XY: 135916

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.00179

Gnomad SAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0520 AC: 76044 AN: 1461876 Hom.: 2330 Cov.: 31 AF XY: 0.0509 AC XY: 37040 AN XY: 727240

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.0520

Gnomad4 EAS exome AF: 0.000932

Gnomad4 SAS exome AF: 0.0255

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0541

Gnomad4 OTH exome AF: 0.0572

GnomAD4 genome AF: 0.0769 AC: 11706 AN: 152238 Hom.: 636 Cov.: 32 AF XY: 0.0740 AC XY: 5506 AN XY: 74422

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0470

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0278

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.0652

Alfa AF: 0.0589 Hom.: 439

Bravo AF: 0.0820

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.158 AC: 696

ESP6500EA AF: 0.0579 AC: 498

ExAC AF: 0.0510 AC: 6188

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.0586

EpiControl AF: 0.0555

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Duane-radial ray syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.12
DANN	Benign	0.72
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.018
Sift	Benign	0.67	T
Sift4G	Benign	0.96	T
Polyphen		0.0010	B
Vest4		0.040
MPC		0.33
ClinPred		0.0033	T
GERP RS		-5.1
Varity_R		0.060
gMVP		0.13

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: rs6091375; hg19: chr20-50406630;