Genetic Variant SALL3:p.Val52Leu (chr18-78992145-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_171999.4(SALL3):c.154G>T(p.Val52Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SALL3
NM_171999.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.73

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]

SALL3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL3	NM_171999.4 link	c.154G>T	p.Val52Leu	missense_variant	Exon 2 of 3	ENST00000537592.7	NP_741996.2	Q9BXA9-1A9JR48A0A384MEH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SALL3	ENST00000537592.7 link	c.154G>T	p.Val52Leu	missense_variant	Exon 2 of 3	5	NM_171999.4	ENSP00000441823.2		Q9BXA9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000846

AC:

AN:

236386

Hom.:

AF XY:

0.00000775

AC XY:

AN XY:

129022

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

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:

0.00000946

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455018

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723568

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

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:

0.0000333

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.154G>T (p.V52L) alteration is located in exon 2 (coding exon 2) of the SALL3 gene. This alteration results from a G to T substitution at nucleotide position 154, causing the valine (V) at amino acid position 52 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

0.25

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

T;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.8

.;M;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.2

.;.;N

REVEL

Benign

0.20

Sift

Uncertain

0.0070

.;.;D

Sift4G

Benign

0.25

T;D;D

Polyphen

1.0

.;.;D

Vest4

0.55

MutPred

0.41

Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);

MVP

0.69

MPC

0.39

ClinPred

0.86

GERP RS

4.4

Varity_R

0.23

gMVP

0.11

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