rs750281602

chr8-22419626-C-Gchr8-22419626-C-T

Variant summary

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

The NM_015359.6(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). Synonymous variant affecting the same amino acid position (i.e. N469N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A14 NM_015359.6 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	UniProt
SLC39A14	NM_001128431.4	c.1407C>G	p.Asn469Lys	missense_variant	9/9	ENST00000381237.6
SLC39A14	NM_015359.6	c.1407C>G	p.Asn469Lys	missense_variant	9/9	ENST00000359741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A14	ENST00000359741.10	c.1407C>G	p.Asn469Lys	missense_variant	9/9	2	NM_015359.6	A2
SLC39A14	ENST00000381237.6	c.1407C>G	p.Asn469Lys	missense_variant	9/9	1	NM_001128431.4	P4
SLC39A14	ENST00000240095.10	c.1332+1791C>G		intron_variant		1
SLC39A14	ENST00000289952.9	c.1407C>G	p.Asn469Lys	missense_variant	9/9	2		P4

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
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
MutationTaster	Benign	1.0	D;D;D;D
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;