rs750281602

Positions:

• chr8-22419626-C-G
• chr8-22419626-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001128431.4(SLC39A14):​c.1407C>G​(p.Asn469Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A14 NM_001128431.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.870

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 8-22419626-C-G is Pathogenic according to our data. Variant chr8-22419626-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 242928.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22419626-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.1407C>G	p.Asn469Lys	missense_variant	9/9	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.1407C>G	p.Asn469Lys	missense_variant	9/9	ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.1407C>G	p.Asn469Lys	missense_variant	9/9	2	NM_015359.6	ENSP00000352779.5
SLC39A14	ENST00000381237.6	c.1407C>G	p.Asn469Lys	missense_variant	9/9	1	NM_001128431.4	ENSP00000370635.1
SLC39A14	ENST00000240095.10	c.1332+1791C>G		intron_variant		1		ENSP00000240095.6
SLC39A14	ENST00000289952.9	c.1407C>G	p.Asn469Lys	missense_variant	9/9	2		ENSP00000289952.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypermanganesemia with dystonia 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.91
MutPred		0.82		Gain of ubiquitination at N469 (P = 0.0311);Gain of ubiquitination at N469 (P = 0.0311);Gain of ubiquitination at N469 (P = 0.0311);
MVP		0.43
MPC		1.6
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs750281602; hg19: chr8-22277139;