4-42065323-TAGC-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. 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 (★).

• 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: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC30A9	NM_006345.4	c.1049_1051delCAG	p.Ala350del	disruptive_inframe_deletion	Exon 12 of 18	ENST00000264451.12	NP_006336.3
SLC30A9	XM_047449525.1	c.1049_1051delCAG	p.Ala350del	disruptive_inframe_deletion	Exon 12 of 13		XP_047305481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC30A9	ENST00000264451.12	c.1049_1051delCAG	p.Ala350del	disruptive_inframe_deletion	Exon 12 of 18	1	NM_006345.4	ENSP00000264451.6
SLC30A9	ENST00000509683.5	n.105_107delCAG		non_coding_transcript_exon_variant	Exon 2 of 6	3
SLC30A9	ENST00000513699.5	n.*806_*808delCAG		non_coding_transcript_exon_variant	Exon 13 of 19	2		ENSP00000423529.1
SLC30A9	ENST00000513699.5	n.*806_*808delCAG		3_prime_UTR_variant	Exon 13 of 19	2		ENSP00000423529.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome Pathogenic:2

May 04, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 08, 2023

UAEU Genomics Laboratory, United Arab Emirates University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The in-frame deletion NM_006345.4(SLC30A9):c.1049_1051delCAG (p.Ala350del) has been reported previously in 6 individuals from a Bedouin kindred affected with Birk-Landau-Perez syndrome (Perez et al., 2017). This variant is not present in gnomAD database (Karczewski et al., 2020) and Middle Eastern specific databases (Koshy et al., 2017). The removed amino acid is highly conserved and is located at the predicted cation-efflux domain of the mature SLC30A9 protein. 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).Further, in CRISPR-Cas9 knockout (SLC30A9 -/-) cell lines, functional complementation of the p.Ala350Del variant failed to restore the functional defect caused by genetic ablation of SLC30A9, indicating that the p.Ala350Del variant is a loss-of-function allele (Deng et al., 2021). Aggregating all the available evidence (PM2, PM1, PS3, PP1_strong), this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;