rs779241085

Positions:

chr4-102305054-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The NM_001135146.2(SLC39A8):c.610G>T(p.Gly204Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000534 in 1,610,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G204V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SLC39A8
NM_001135146.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 5.34

Variant links:

Genes affected

SLC39A8 (HGNC:20862): (solute carrier family 39 member 8) This gene encodes a member of the SLC39 family of solute-carrier genes, which show structural characteristics of zinc transporters. The encoded protein is glycosylated and found in the plasma membrane and mitochondria, and functions in the cellular import of zinc at the onset of inflammation. It is also thought to be the primary transporter of the toxic cation cadmium, which is found in cigarette smoke. Multiple transcript variants encoding different isoforms have been found for this gene. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Oct 2008]

SLC39A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-102305053-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1304789.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

PP5

Variant 4-102305054-C-A is Pathogenic according to our data. Variant chr4-102305054-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218897.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2, Pathogenic=1}. Variant chr4-102305054-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A8	NM_001135146.2 linkuse as main transcript	c.610G>T	p.Gly204Cys	missense_variant	5/9	ENST00000356736.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A8	ENST00000356736.5 linkuse as main transcript	c.610G>T	p.Gly204Cys	missense_variant	5/9	1	NM_001135146.2	P1	Q9C0K1-1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000642

AC:

AN:

249194

Hom.:

AF XY:

0.0000668

AC XY:

AN XY:

134808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1458526

Hom.:

Cov.:

AF XY:

0.0000524

AC XY:

AN XY:

725662

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000667

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74056

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000885

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2023	Published functional studies suggest a damaging effect (Choi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28557351, 30090406, 28749473, 29453449, 32753748, 26637979, 34768831) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 204 of the SLC39A8 protein (p.Gly204Cys). This variant is present in population databases (rs779241085, gnomAD 0.01%). This missense change has been observed in individual(s) with SLC39A8-congenital disorder of glycosylation (PMID: 26637979). ClinVar contains an entry for this variant (Variation ID: 218897). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SLC39A8 function (PMID: 34768831). 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. -

SLC39A8-CDG

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 28, 2023

Variant summary: SLC39A8 c.610G>T (p.Gly204Cys) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved residue. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249194 control chromosomes (gnomAD). c.610G>T has been reported in the literature in a compound heterozygous individual who was affected with manganese transport- and glycosylation defects, where manganese supplementation resulted in clinical improvement (Park_2015, Park_2018). These data do not allow clear conclusions about variant significance. A recent study reported that the variant in isolation resulted in reduced selenium transport (Liang_2021), similarly to other tested SLC39A8 variants (including the missense reported in trans Park_2015). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.0

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.3

D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.056

T;T;T

Polyphen

0.98

.;D;D

Vest4

0.72

MVP

0.45

MPC

1.3

ClinPred

0.82

GERP RS

5.3

Varity_R

0.88

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over