8-22415760-C-G

Position:

• chr8-22415760-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_015359.6(SLC39A14):​c.751-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A14 NM_015359.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -0.475

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-22415760-C-G is Pathogenic according to our data. Variant chr8-22415760-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446707.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-22415760-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A14	NM_001128431.4	c.751-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381237.6
SLC39A14	NM_015359.6	c.751-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A14	ENST00000359741.10	c.751-9C>G		splice_polypyrimidine_tract_variant, intron_variant		2	NM_015359.6	A2
SLC39A14	ENST00000381237.6	c.751-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001128431.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypermanganesemia with dystonia 2 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	The homozygous c.751-9C>G variant in SLC39A14 was identified by our study in 1 individual with hypermanganesemia with dystonia 2. This variant has also been reported in the same individual as well as one other Emirati individual with hypermanganesemia with dystonia 2 (PMID: 29685658), but was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 446707) and has been interpreted as pathogenic by GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK431123/). The presence of this variant in 2 affected homozygotes and in 2 individuals with hypermanganesemia with dystonia 2 increases the likelihood that the variant is pathogenic (PMID: 29685658). In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 29685658). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PS3_supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 28, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	21
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 1
DS_AL_spliceai		0.69		Position offset: 9

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

Publications

LitVar

Other links and lift over

dbSNP: rs1039778197; hg19: chr8-22273273;