rs1131692331

Variant names:

• chr4-42065323-TAGC-T
• rs1131692331
• NM_006345.4:c.1049_1051delCAG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PM4_Supporting PP5_Moderate

The NM_006345.4(SLC30A9):​c.1049_1051delCAG​(p.Ala350del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003923319: "In vitro functional studies in human neuroblastoma cells showed a significant decrease in cytosolic free Zn2+ levels in cells expressing the mutant compared to the wild type." (Perez et al., 2017).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC30A9 NM_006345.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.79
• Publications: 4 publications found

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]

SLC30A9 Gene-Disease associations (from GenCC):

• psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003923319: "In vitro functional studies in human neuroblastoma cells showed a significant decrease in cytosolic free Zn2+ levels in cells expressing the mutant compared to the wild type." (Perez et al., 2017).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006345.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 4-42065323-TAGC-T is Pathogenic according to our data. Variant chr4-42065323-TAGC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 431049.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006345.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC30A9	NM_006345.4	MANE Select	c.1049_1051delCAG	p.Ala350del	disruptive_inframe_deletion	Exon 12 of 18	NP_006336.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC30A9	ENST00000264451.12	TSL:1 MANE Select	c.1049_1051delCAG	p.Ala350del	disruptive_inframe_deletion	Exon 12 of 18	ENSP00000264451.6	Q6PML9
	SLC30A9	ENST00000866307.1		c.1046_1048delCAG	p.Ala349del	disruptive_inframe_deletion	Exon 12 of 18	ENSP00000536366.1
	SLC30A9	ENST00000962779.1		c.1043_1045delCAG	p.Ala348del	disruptive_inframe_deletion	Exon 12 of 18	ENSP00000632838.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1131692331; hg19: chr4-42067340;