rs879253763

Positions:

• chr8-22408331-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000381237.6(SLC39A14):​c.292T>G​(p.Phe98Val) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A14 ENST00000381237.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.22

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22408331-T-G is Pathogenic according to our data. Variant chr8-22408331-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 242924.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22408331-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.40299124). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.292T>G	p.Phe98Val	missense_variant	3/9	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.292T>G	p.Phe98Val	missense_variant	3/9	ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.292T>G	p.Phe98Val	missense_variant	3/9	2	NM_015359.6	ENSP00000352779	A2
SLC39A14	ENST00000381237.6	c.292T>G	p.Phe98Val	missense_variant	3/9	1	NM_001128431.4	ENSP00000370635	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	0.73
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	.;.;T;T;T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D
Polyphen		0.57, 0.90	.;P;P;P;.;.;.
Vest4		0.85
MutPred		0.31		Gain of glycosylation at S94 (P = 0.2243);Gain of glycosylation at S94 (P = 0.2243);Gain of glycosylation at S94 (P = 0.2243);Gain of glycosylation at S94 (P = 0.2243);Gain of glycosylation at S94 (P = 0.2243);Gain of glycosylation at S94 (P = 0.2243);Gain of glycosylation at S94 (P = 0.2243);
MVP		0.45
MPC		1.2
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs879253763; hg19: chr8-22265844;