4-42060207-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006345.4(SLC30A9):c.857G>A(p.Gly286Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SLC30A9 NM_006345.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14

Genes affected

SLC30A9 (HGNC:1329): (solute carrier family 30 member 9) Predicted to enable nuclear receptor coactivator activity. Involved in cellular zinc ion homeostasis and zinc ion transport. Located in several cellular components, including cytoplasmic vesicle; cytoskeleton; and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC30A9	NM_006345.4	c.857G>A	p.Gly286Asp	missense_variant	10/18	ENST00000264451.12
SLC30A9	XM_047449525.1	c.857G>A	p.Gly286Asp	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC30A9	ENST00000264451.12	c.857G>A	p.Gly286Asp	missense_variant	10/18	1	NM_006345.4	P1
SLC30A9	ENST00000513699.5	c.*614G>A		3_prime_UTR_variant, NMD_transcript_variant	11/19	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74232

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2021

The c.857G>A (p.G286D) alteration is located in exon 10 (coding exon 10) of the SLC30A9 gene. This alteration results from a G to A substitution at nucleotide position 857, causing the glycine (G) at amino acid position 286 to be replaced by an aspartic acid (D). 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	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.77		Loss of ubiquitination at K289 (P = 0.0561);
MVP		0.81
MPC		1.5
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1222039958; hg19: chr4-42062224;