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GeneBe

18-78992722-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_171999.4(SALL3):c.731C>T(p.Pro244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000565 in 1,416,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

SALL3
NM_171999.4 missense

Scores

2
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59
Variant links:
Genes affected
SALL3 (HGNC:10527): (spalt like transcription factor 3) This gene encodes a sal-like C2H2-type zinc-finger protein, and belongs to a family of evolutionarily conserved genes found in species as diverse as Drosophila, C. elegans, and vertebrates. Mutations in some of these genes are associated with congenital disorders in human, suggesting their importance in embryonic development. This protein binds to DNA methyltransferase 3 alpha (DNMT3A), and reduces DNMT3A-mediated CpG island methylation. It is suggested that silencing of this gene, resulting in acceleration of DNA methylation, may have a role in oncogenesis. [provided by RefSeq, Oct 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13301918).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SALL3NM_171999.4 linkuse as main transcriptc.731C>T p.Pro244Leu missense_variant 2/3 ENST00000537592.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SALL3ENST00000537592.7 linkuse as main transcriptc.731C>T p.Pro244Leu missense_variant 2/35 NM_171999.4 P1Q9BXA9-1
SALL3ENST00000575389.6 linkuse as main transcriptc.731C>T p.Pro244Leu missense_variant 2/45 Q9BXA9-2
SALL3ENST00000536229.7 linkuse as main transcriptc.332C>T p.Pro111Leu missense_variant 1/33 Q9BXA9-3

Frequencies

GnomAD3 genomes
AF:
0.0000271
AC:
4
AN:
147802
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000977
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD4 exome
AF:
0.00000315
AC:
4
AN:
1268992
Hom.:
0
Cov.:
30
AF XY:
0.00000319
AC XY:
2
AN XY:
626866
show subpopulations
Gnomad4 AFR exome
AF:
0.0000405
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:
0.00000295
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000271
AC:
4
AN:
147802
Hom.:
0
Cov.:
33
AF XY:
0.0000417
AC XY:
3
AN XY:
71976
show subpopulations
Gnomad4 AFR
AF:
0.0000977
Gnomad4 AMR
AF:
0.00
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
Bravo
AF:
0.0000416
ExAC
AF:
0.0000413
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 28, 2021The c.731C>T (p.P244L) alteration is located in exon 2 (coding exon 2) of the SALL3 gene. This alteration results from a C to T substitution at nucleotide position 731, causing the proline (P) at amino acid position 244 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
Cadd
Benign
21
Dann
Benign
0.89
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.58
T;T;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.71
T
Sift4G
Uncertain
0.022
D;D;D
Polyphen
0.42
.;B;.
Vest4
0.086
MutPred
0.18
Loss of glycosylation at P244 (P = 0.0225);Loss of glycosylation at P244 (P = 0.0225);.;
MVP
0.38
MPC
0.40
ClinPred
0.37
T
GERP RS
0.85
Varity_R
0.081
gMVP
0.31

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.

Other links and lift over

dbSNP: rs765021006; hg19: chr18-76752722; API