8-22404715-A-AGCTGCT

Position:

• chr8-22404715-A-AGCTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000381237.6(SLC39A14):​c.14_19dup​(p.Leu5_Leu6dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SLC39A14 ENST00000381237.6 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

SLC39A14 (HGNC:20858): (solute carrier family 39 member 14) This gene encodes a member of the the SLC39A family of divalent metal transporters that mediates the cellular uptake of manganese, zinc, iron, and cadmium. The encoded protein contains eight transmembrane domains, a histidine-rich motif, and a metalloprotease motif, and is expressed on the plasma membrane and the endocytic vesicle membrane. It is an important transporter of nontransferrin-bound iron and a critical regulator of manganese homeostasis. Naturally occurring mutations in this gene are associated with neurodegeneration with brain iron accumulation and early-onset parkinsonism-dystonia with hypermanganesemia. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000381237.6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.14_19dup	p.Leu5_Leu6dup	inframe_insertion	2/9	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.14_19dup	p.Leu5_Leu6dup	inframe_insertion	2/9	ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.14_19dup	p.Leu5_Leu6dup	inframe_insertion	2/9	2	NM_015359.6	ENSP00000352779	A2
SLC39A14	ENST00000381237.6	c.14_19dup	p.Leu5_Leu6dup	inframe_insertion	2/9	1	NM_001128431.4	ENSP00000370635	P4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

This variant is not present in population databases (gnomAD no frequency). This variant, c.14_19dup, results in the insertion of 2 amino acid(s) of the SLC39A14 protein (p.Leu5_Leu6dup), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with SLC39A14-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr8-22262228;