18-78992451-C-G

Variant names:

• chr18-78992451-C-G
• rs1481037663
• NM_171999.4:c.460C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_171999.4(SALL3):​c.460C>G​(p.Pro154Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,424,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P154S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.760
• Publications: 0 publications found

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042712003).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_171999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL3	NM_171999.4	MANE Select	c.460C>G	p.Pro154Ala	missense	Exon 2 of 3	NP_741996.2	Q9BXA9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL3	ENST00000537592.7	TSL:5 MANE Select	c.460C>G	p.Pro154Ala	missense	Exon 2 of 3	ENSP00000441823.2	Q9BXA9-1
	SALL3	ENST00000575389.6	TSL:5	c.460C>G	p.Pro154Ala	missense	Exon 2 of 4	ENSP00000458360.2	Q9BXA9-2
	SALL3	ENST00000536229.7	TSL:3	c.61C>G	p.Pro21Ala	missense	Exon 1 of 3	ENSP00000439975.3	Q9BXA9-3

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149932 Hom.: 0 Cov.: 33

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 28 AN: 1274348 Hom.: 0 Cov.: 30 AF XY: 0.00000955 AC XY: 6 AN XY: 628126

African (AFR) AF: 0.00 AC: 0 AN: 24320

American (AMR) AF: 0.00 AC: 0 AN: 20242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20390

East Asian (EAS) AF: 0.00 AC: 0 AN: 25136

South Asian (SAS) AF: 0.00 AC: 0 AN: 70010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3690

European-Non Finnish (NFE) AF: 0.0000273 AC: 28 AN: 1027118

Other (OTH) AF: 0.00 AC: 0 AN: 51630

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149932 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73120

African (AFR) AF: 0.00 AC: 0 AN: 41230

American (AMR) AF: 0.00 AC: 0 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67232

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.9
DANN	Benign	0.57
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.76
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.019
Sift	Benign	0.26	T
Sift4G	Benign	0.62	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.20		Loss of glycosylation at P154 (P = 0.0025)
MVP		0.088
MPC		0.38
ClinPred		0.31	T
GERP RS		1.1
Varity_R		0.023
gMVP		0.28
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

Other links and lift over

dbSNP: rs1481037663; hg19: chr18-76752451;