chr8-22416280-G-A

Variant names:

• chr8-22416280-G-A
• rs879253766
• NM_001128431.4:c.1147G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001128431.4(SLC39A14):​c.1147G>A​(p.Gly383Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC39A14 NM_001128431.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.83
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 8-22416280-G-A is Pathogenic according to our data. Variant chr8-22416280-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 242927.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1147G>A	p.Gly383Arg	missense splice_region	Exon 7 of 9	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.1147G>A	p.Gly383Arg	missense splice_region	Exon 7 of 9	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.1177G>A	p.Gly393Arg	missense splice_region	Exon 9 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.1147G>A	p.Gly383Arg	missense splice_region	Exon 7 of 9	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.1147G>A	p.Gly383Arg	missense splice_region	Exon 7 of 9	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.1147G>A	p.Gly383Arg	missense splice_region	Exon 7 of 9	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460328 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726490

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4622

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60254

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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.78
Sift	Benign	0.059	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.89		Gain of methylation at G383 (P = 0.0663)
MVP		0.67
MPC		1.7
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.60
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.13		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: rs879253766; hg19: chr8-22273793;