18-78980330-T-C

Position:

• chr18-78980330-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_171999.4(SALL3):​c.56T>C​(p.Leu19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,289,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: SALL3 NM_171999.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.478

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053854823).
• BP6: Variant 18-78980330-T-C is Benign according to our data. Variant chr18-78980330-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2516886.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL3	NM_171999.4	c.56T>C	p.Leu19Pro	missense_variant	1/3	ENST00000537592.7	NP_741996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL3	ENST00000537592.7	c.56T>C	p.Leu19Pro	missense_variant	1/3	5	NM_171999.4	ENSP00000441823	P1
SALL3	ENST00000575389.6	c.56T>C	p.Leu19Pro	missense_variant	1/4	5		ENSP00000458360

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1289940 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 635770

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: 9.77e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Benign	0.49
DEOGEN2	Benign	0.0039	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.089	T;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.97	.;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.38	.;.;N
REVEL	Benign	0.038
Sift	Benign	0.21	.;.;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.12
MutPred		0.26		Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);
MVP		0.17
MPC		0.64
ClinPred		0.039	T
GERP RS		-3.3
Varity_R		0.062
gMVP		0.10

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: chr18-76740330;