18-78992728-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_171999.4(SALL3):c.737C>T(p.Ala246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,375,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SALL3
NM_171999.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.227

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09479037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL3	NM_171999.4 link	c.737C>T	p.Ala246Val	missense_variant	Exon 2 of 3	ENST00000537592.7	NP_741996.2	Q9BXA9-1A9JR48A0A384MEH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SALL3	ENST00000537592.7 link	c.737C>T	p.Ala246Val	missense_variant	Exon 2 of 3	5	NM_171999.4	ENSP00000441823.2	Q9BXA9-1
SALL3	ENST00000575389.6 link	c.737C>T	p.Ala246Val	missense_variant	Exon 2 of 4	5		ENSP00000458360.2	Q9BXA9-2
SALL3	ENST00000536229.7 link	c.338C>T	p.Ala113Val	missense_variant	Exon 1 of 3	3		ENSP00000439975.3	Q9BXA9-3

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

147082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000171

AC:

AN:

58404

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000617

GnomAD4 exome

AF:

0.0000106

AC:

AN:

1228880

Hom.:

Cov.:

AF XY:

0.00000661

AC XY:

AN XY:

605538

show subpopulations

Gnomad4 AFR exome

AF:

0.0000428

AC:

AN:

23370

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

19046

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

18054

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

22504

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

67704

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

30120

Gnomad4 NFE exome

AF:

0.0000120

AC:

AN:

996494

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

48190

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000136

AC:

AN:

147082

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71600

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000302

AC:

0.0000301805

AN:

0.0000301805

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.737C>T (p.A246V) 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 737, causing the alanine (A) at amino acid position 246 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.3

DANN

Benign

0.92

DEOGEN2

Benign

0.061

.;T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.49

T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.095

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

L;L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

.;N;.

REVEL

Benign

0.032

Sift

Benign

0.26

.;T;.

Sift4G

Benign

0.32

T;T;T

Polyphen

0.81

.;P;.

Vest4

0.12

MutPred

0.19

Loss of glycosylation at P244 (P = 0.0972);Loss of glycosylation at P244 (P = 0.0972);.;

MVP

0.28

MPC

0.39

ClinPred

0.077

GERP RS

-0.13

Varity_R

0.054

gMVP

0.37

Mutation Taster

=99/1

polymorphism

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