18-78992770-G-C

Variant names:

• chr18-78992770-G-C
• rs1018465445
• NM_171999.4:c.779G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_171999.4(SALL3):​c.779G>C​(p.Gly260Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,037,688 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13644761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL3	NM_171999.4	c.779G>C	p.Gly260Ala	missense_variant	Exon 2 of 3	ENST00000537592.7	NP_741996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SALL3	ENST00000537592.7	c.779G>C	p.Gly260Ala	missense_variant	Exon 2 of 3	5	NM_171999.4	ENSP00000441823.2
SALL3	ENST00000575389.6	c.779G>C	p.Gly260Ala	missense_variant	Exon 2 of 4	5		ENSP00000458360.2
SALL3	ENST00000536229.7	c.380G>C	p.Gly127Ala	missense_variant	Exon 1 of 3	3		ENSP00000439975.3

Frequencies

GnomAD3 genomes AF: 0.000226 AC: 33 AN: 146168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000735

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: 0.000425

Gnomad OTH AF: 0.000995

GnomAD4 exome AF: 0.000436 AC: 389 AN: 891520 Hom.: 0 Cov.: 28 AF XY: 0.000422 AC XY: 176 AN XY: 416698

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 16686

Gnomad4 AMR exome AF: 0.000389 AC: 1 AN: 2572

Gnomad4 ASJ exome AF: 0.000153 AC: 1 AN: 6538

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 8138

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 18046

Gnomad4 FIN exome AF: 0.000124 AC: 1 AN: 8074

Gnomad4 NFE exome AF: 0.000472 AC: 377 AN: 799048

Gnomad4 Remaining exome AF: 0.000295 AC: 9 AN: 30534

GnomAD4 genome AF: 0.000226 AC: 33 AN: 146168 Hom.: 1 Cov.: 32 AF XY: 0.000211 AC XY: 15 AN XY: 71044

Gnomad4 AFR AF: 0.0000735 AC: 0.0000735438 AN: 0.0000735438

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000425 AC: 0.000425351 AN: 0.000425351

Gnomad4 OTH AF: 0.000995 AC: 0.000995025 AN: 0.000995025

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000261

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.779G>C (p.G260A) alteration is located in exon 2 (coding exon 2) of the SALL3 gene. This alteration results from a G to C substitution at nucleotide position 779, causing the glycine (G) at amino acid position 260 to be replaced by an alanine (A). 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	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.65
DEOGEN2	Benign	0.036	.;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.89	L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.14	.;N;.
REVEL	Benign	0.13
Sift	Benign	0.49	.;T;.
Sift4G	Benign	0.48	T;T;T
Polyphen		0.30	.;B;.
Vest4		0.31
MutPred		0.17		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.43
MPC		0.43
ClinPred		0.25	T
GERP RS		3.5
Varity_R		0.085
gMVP		0.43
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs1018465445; hg19: chr18-76752770;