Genetic Variant NM_171999.4:c.2254G>T (chr18-78994245-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_171999.4(SALL3):c.2254G>T(p.Val752Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V752M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SALL3
NM_171999.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.83

Publications

0 publications found

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40240854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL3	NM_171999.4 link	c.2254G>T	p.Val752Leu	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.2254G>T	p.Val752Leu	missense_variant	Exon 2 of 3	5	NM_171999.4	ENSP00000441823.2	Q9BXA9-1
SALL3	ENST00000575389.6 link	c.2254G>T	p.Val752Leu	missense_variant	Exon 2 of 4	5		ENSP00000458360.2	Q9BXA9-2
SALL3	ENST00000536229.7 link	c.1855G>T	p.Val619Leu	missense_variant	Exon 1 of 3	3		ENSP00000439975.3	Q9BXA9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.077

T;.;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.078

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Uncertain

-0.052

MutationAssessor

Benign

0.38

.;N;N;.

PhyloP100

6.8

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.4

.;.;N;.

REVEL

Uncertain

0.50

Sift

Uncertain

0.0060

.;.;D;.

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.99

.;.;D;.

Vest4

0.41

MutPred

0.52

.;Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);.;

MVP

0.86

MPC

1.1

ClinPred

0.88

GERP RS

5.2

Varity_R

0.34

gMVP

0.44

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over