chr18-78992412-G-T

Variant names:

• chr18-78992412-G-T
• rs933317887
• NM_171999.4:c.421G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_171999.4(SALL3):​c.421G>T​(p.Asp141Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,180,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D141N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63
• 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: 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=0.27720124).

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.421G>T	p.Asp141Tyr	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.421G>T	p.Asp141Tyr	missense	Exon 2 of 3	ENSP00000441823.2	Q9BXA9-1
	SALL3	ENST00000575389.6	TSL:5	c.421G>T	p.Asp141Tyr	missense	Exon 2 of 4	ENSP00000458360.2	Q9BXA9-2
	SALL3	ENST00000536229.7	TSL:3	c.22G>T	p.Asp8Tyr	missense	Exon 1 of 3	ENSP00000439975.3	Q9BXA9-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000119 AC: 14 AN: 1180114 Hom.: 0 Cov.: 30 AF XY: 0.0000157 AC XY: 9 AN XY: 574774

African (AFR) AF: 0.00 AC: 0 AN: 22054

American (AMR) AF: 0.00 AC: 0 AN: 8086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14586

East Asian (EAS) AF: 0.00 AC: 0 AN: 23578

South Asian (SAS) AF: 0.00 AC: 0 AN: 52096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3216

European-Non Finnish (NFE) AF: 0.0000143 AC: 14 AN: 981120

Other (OTH) AF: 0.00 AC: 0 AN: 47128

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.057	T
Eigen	Benign	0.033
Eigen_PC	Benign	0.0011
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.062	T
Sift4G	Uncertain	0.056	T
Polyphen		0.96	P
Vest4		0.45
MutPred		0.21		Gain of phosphorylation at D141 (P = 0.0042)
MVP		0.51
MPC		0.49
ClinPred		0.84	D
GERP RS		3.9
Varity_R		0.18
gMVP		0.21
Mutation Taster		=82/18	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: rs933317887; hg19: chr18-76752412;