chr6-28575396-C-G

Position:

• chr6-28575396-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_052923.2(SCAND3):​c.1309G>C​(p.Asp437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCAND3 NM_052923.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.704

Genes affected

SCAND3 (HGNC:13851): (SCAN domain containing 3) Predicted to enable nucleic acid binding activity. Involved in positive regulation of cell cycle and positive regulation of epithelial cell proliferation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCAND3	NM_052923.2	c.1309G>C	p.Asp437His	missense_variant	3/4	ENST00000452236.3	NP_443155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCAND3	ENST00000452236.3	c.1309G>C	p.Asp437His	missense_variant	3/4	1	NM_052923.2	ENSP00000395259.2
SCAND3	ENST00000646382.1	c.856G>C	p.Asp286His	missense_variant	4/5			ENSP00000494942.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461742 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 15, 2024

The c.1309G>C (p.D437H) alteration is located in exon 3 (coding exon 3) of the ZBED9 gene. This alteration results from a G to C substitution at nucleotide position 1309, causing the aspartic acid (D) at amino acid position 437 to be replaced by a histidine (H). 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	0.20
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.19	.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	.;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	.;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		0.43	.;B
Vest4		0.32
MutPred		0.93		.;Gain of catalytic residue at N438 (P = 0.0898);
MVP		0.57
MPC		0.59
ClinPred		0.17	T
GERP RS		-2.0
Varity_R		0.090
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs1764362125; hg19: chr6-28543173;