18-78992208-T-A

Position:

• chr18-78992208-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_171999.4(SALL3):​c.217T>A​(p.Cys73Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL3	NM_171999.4	c.217T>A	p.Cys73Ser	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.217T>A	p.Cys73Ser	missense_variant	2/3	5	NM_171999.4	ENSP00000441823	P1
SALL3	ENST00000575389.6	c.217T>A	p.Cys73Ser	missense_variant	2/4	5		ENSP00000458360
SALL3	ENST00000536229.7	c.-183T>A		5_prime_UTR_variant	1/3	3		ENSP00000439975
SALL3	ENST00000572928.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Jun 18, 2024

The c.217T>A (p.C73S) alteration is located in exon 2 (coding exon 2) of the SALL3 gene. This alteration results from a T to A substitution at nucleotide position 217, causing the cysteine (C) at amino acid position 73 to be replaced by a serine (S). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T;.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;T;T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.4	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.4	.;.;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	.;.;D
Sift4G	Benign	0.32	T;D;D
Polyphen		1.0	.;.;D
Vest4		0.88
MutPred		0.67		Gain of glycosylation at C73 (P = 0.0243);Gain of glycosylation at C73 (P = 0.0243);Gain of glycosylation at C73 (P = 0.0243);
MVP		0.72
MPC		0.49
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.083

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: chr18-76752208;