20-51784329-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020436.5(SALL4):c.3098C>T(p.Thr1033Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1033A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SALL4
NM_020436.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13615403).

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SALL4	NM_020436.5 linkuse as main transcript	c.3098C>T	p.Thr1033Ile	missense_variant	4/4	ENST00000217086.9
SALL4	NM_001318031.2 linkuse as main transcript	c.1787C>T	p.Thr596Ile	missense_variant	4/4
SALL4	XM_047440318.1 linkuse as main transcript	c.2792C>T	p.Thr931Ile	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL4	ENST00000217086.9 linkuse as main transcript	c.3098C>T	p.Thr1033Ile	missense_variant	4/4	1	NM_020436.5	P1	Q9UJQ4-1
SALL4	ENST00000395997.3 linkuse as main transcript	c.1787C>T	p.Thr596Ile	missense_variant	4/4	1			Q9UJQ4-2
SALL4	ENST00000371539.7 linkuse as main transcript	c.767C>T	p.Thr256Ile	missense_variant	3/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000945

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.3098C>T (p.T1033I) alteration is located in exon 4 (coding exon 4) of the SALL4 gene. This alteration results from a C to T substitution at nucleotide position 3098, causing the threonine (T) at amino acid position 1033 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SALL4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

The SALL4 c.3098C>T variant is predicted to result in the amino acid substitution p.Thr1033Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.086

Sift

Benign

0.15

T;D;T

Sift4G

Uncertain

0.060

T;T;T

Polyphen

0.090

B;B;.

Vest4

0.031

MutPred

0.38

Loss of glycosylation at T1033 (P = 0.0121);.;.;

MVP

0.44

MPC

0.38

ClinPred

0.30

GERP RS

4.6

Varity_R

0.064

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over