8-22404774-T-C

Position:

• chr8-22404774-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015359.6(SLC39A14):​c.64T>C​(p.Trp22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC39A14 NM_015359.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.64T>C	p.Trp22Arg	missense_variant	2/9	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.64T>C	p.Trp22Arg	missense_variant	2/9	ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.64T>C	p.Trp22Arg	missense_variant	2/9	2	NM_015359.6	ENSP00000352779	A2
SLC39A14	ENST00000381237.6	c.64T>C	p.Trp22Arg	missense_variant	2/9	1	NM_001128431.4	ENSP00000370635	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251328 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461108 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2022

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 22 of the SLC39A14 protein (p.Trp22Arg). This variant is present in population databases (rs751325399, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SLC39A14-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.12	.;T;.;T;T;T;.;T;T;T
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.65	T;T;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	M;.;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N;D;N;N;N;D;D;D;D;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.40	T;D;T;T;T;D;D;D;D;D
Polyphen		0.93, 0.61	.;.;P;P;P;.;.;.;.;.
Vest4		0.43
MutPred		0.71		Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);
MVP		0.53
MPC		1.7
ClinPred		0.48	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
gMVP		0.57

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: rs751325399; hg19: chr8-22262287; COSMIC: COSV105004539;