rs879253764

Positions:

• chr8-22408352-G-A
• chr8-22408352-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001128431.4(SLC39A14):​c.313G>A​(p.Glu105Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC39A14 NM_001128431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.453

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_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047558457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.313G>A	p.Glu105Lys	missense_variant	3/9	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.313G>A	p.Glu105Lys	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.313G>A	p.Glu105Lys	missense_variant	3/9	2	NM_015359.6	ENSP00000352779.5
SLC39A14	ENST00000381237.6	c.313G>A	p.Glu105Lys	missense_variant	3/9	1	NM_001128431.4	ENSP00000370635.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.092	.;.;T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Uncertain	0.92	D;D;.;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.048	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.65	N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;D;T;T
Polyphen		0.082, 0.020	.;B;B;B;.;.;.
Vest4		0.36
MutPred		0.37		Gain of ubiquitination at E105 (P = 0.0109);Gain of ubiquitination at E105 (P = 0.0109);Gain of ubiquitination at E105 (P = 0.0109);Gain of ubiquitination at E105 (P = 0.0109);Gain of ubiquitination at E105 (P = 0.0109);Gain of ubiquitination at E105 (P = 0.0109);Gain of ubiquitination at E105 (P = 0.0109);
MVP		0.15
MPC		0.64
ClinPred		0.077	T
GERP RS		-8.7
Varity_R		0.030
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs879253764; hg19: chr8-22265865;