chr8-22408331-T-G

Variant names:

• chr8-22408331-T-G
• rs879253763
• NM_001128431.4:c.292T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001128431.4(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 NM_001128431.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.22
• 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hyperostosis cranialis interna

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 242924.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40299124). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A14	NM_001128431.4	MANE Select	c.292T>G	p.Phe98Val	missense	Exon 3 of 9	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.292T>G	p.Phe98Val	missense	Exon 3 of 9	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.322T>G	p.Phe108Val	missense	Exon 5 of 11	NP_001338586.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A14	ENST00000359741.10	TSL:2 MANE Plus Clinical	c.292T>G	p.Phe98Val	missense	Exon 3 of 9	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.292T>G	p.Phe98Val	missense	Exon 3 of 9	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.292T>G	p.Phe98Val	missense	Exon 3 of 9	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypermanganesemia with dystonia 2 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.030	D
Polyphen		0.57	P
Vest4		0.85
MutPred		0.31		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879253763; hg19: chr8-22265844;