18-78992358-G-A

Position:

• chr18-78992358-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_171999.4(SALL3):​c.367G>A​(p.Glu123Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30365372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL3	NM_171999.4	c.367G>A	p.Glu123Lys	missense_variant	2/3	ENST00000537592.7	NP_741996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL3	ENST00000537592.7	c.367G>A	p.Glu123Lys	missense_variant	2/3	5	NM_171999.4	ENSP00000441823.2
SALL3	ENST00000575389.6	c.367G>A	p.Glu123Lys	missense_variant	2/4	5		ENSP00000458360.2
SALL3	ENST00000536229	c.-33G>A		5_prime_UTR_variant	1/3	3		ENSP00000439975.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.29e-7 AC: 1 AN: 1206128 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 585856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.367G>A (p.E123K) alteration is located in exon 2 (coding exon 2) of the SALL3 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the glutamic acid (E) at amino acid position 123 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	0.030
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.72	.;N
REVEL	Benign	0.16
Sift	Benign	0.60	.;T
Sift4G	Benign	0.50	T;T
Polyphen		0.74	.;P
Vest4		0.38
MutPred		0.23		Gain of ubiquitination at E123 (P = 0.0014);Gain of ubiquitination at E123 (P = 0.0014);
MVP		0.76
MPC		0.45
ClinPred		0.35	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-76752358;