18-78980319-C-A

Variant names:

• chr18-78980319-C-A
• rs771517621
• NM_171999.4:c.45C>A

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.45C>A​(p.Asp15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,439,074 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• 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=0.06574169).

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.45C>A	p.Asp15Glu	missense	Exon 1 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.45C>A	p.Asp15Glu	missense	Exon 1 of 3	ENSP00000441823.2	Q9BXA9-1
	SALL3	ENST00000575389.6	TSL:5	c.45C>A	p.Asp15Glu	missense	Exon 1 of 4	ENSP00000458360.2	Q9BXA9-2
	SALL3	ENST00000925065.1		c.45C>A	p.Asp15Glu	missense	Exon 1 of 3	ENSP00000595124.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151320 Hom.: 0 Cov.: 31

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000117 AC: 1 AN: 85754 AF XY: 0.0000206

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: 0.0000336

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000311 AC: 4 AN: 1287754 Hom.: 0 Cov.: 30 AF XY: 0.00000473 AC XY: 3 AN XY: 634668

African (AFR) AF: 0.00 AC: 0 AN: 26104

American (AMR) AF: 0.00 AC: 0 AN: 27870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22116

East Asian (EAS) AF: 0.00 AC: 0 AN: 27188

South Asian (SAS) AF: 0.00 AC: 0 AN: 70860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3694

European-Non Finnish (NFE) AF: 0.00000391 AC: 4 AN: 1022526

Other (OTH) AF: 0.00 AC: 0 AN: 52036

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151320 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73916

African (AFR) AF: 0.00 AC: 0 AN: 41324

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67822

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.047
Sift	Benign	0.70	T
Sift4G	Benign	0.66	T
Polyphen		0.057	B
Vest4		0.12
MutPred		0.16		Gain of helix (P = 0.0199)
MVP		0.31
MPC		0.37
ClinPred		0.13	T
GERP RS		0.73
PromoterAI		-0.0063	Neutral
Varity_R		0.091
gMVP		0.082
Mutation Taster		=95/5	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: rs771517621; hg19: chr18-76740319;