rs750281602

Variant names:

• chr8-22419626-C-G
• rs750281602
• NM_001128431.4:c.1407C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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). 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_001128431.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.870
• Publications: 5 publications found

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]

SLC39A14 Gene-Disease associations (from GenCC):

• hypermanganesemia with dystonia 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• hyperostosis cranialis interna

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 242928.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.1407C>G	p.Asn469Lys	missense_variant	Exon 9 of 9	2	NM_015359.6	ENSP00000352779.5
SLC39A14	ENST00000381237.6	c.1407C>G	p.Asn469Lys	missense_variant	Exon 9 of 9	1	NM_001128431.4	ENSP00000370635.1
SLC39A14	ENST00000240095.10	c.1332+1791C>G		intron_variant	Intron 8 of 8	1		ENSP00000240095.6
SLC39A14	ENST00000289952.9	c.1407C>G	p.Asn469Lys	missense_variant	Exon 9 of 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

May 02, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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
PhyloP100		0.87
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs750281602; hg19: chr8-22277139;