rs121434292

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_130849.4(SLC39A4):c.283C>T(p.Arg95Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000948 in 1,582,794 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.90

Variant links:

Genes affected

SLC39A4 (HGNC:17129): (solute carrier family 39 member 4) This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. Mutations in this gene result in acrodermatitis enteropathica. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

SLC39A4 links:

LOC124902041 (HGNC:):

LOC124902041 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 8-144416001-G-A is Pathogenic according to our data. Variant chr8-144416001-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A4	NM_130849.4 linkuse as main transcript	c.283C>T	p.Arg95Cys	missense_variant	2/12	ENST00000301305.8	NP_570901.3	Q6P5W5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC39A4	ENST00000301305.8 linkuse as main transcript	c.283C>T	p.Arg95Cys	missense_variant	2/12	1	NM_130849.4	ENSP00000301305.4	Q6P5W5-1
SLC39A4	ENST00000276833.9 linkuse as main transcript	c.208C>T	p.Arg70Cys	missense_variant	1/11	2		ENSP00000276833.5	Q6P5W5-2
SLC39A4	ENST00000526658.1 linkuse as main transcript	c.193-582C>T		intron_variant		3		ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000988

AC:

AN:

202420

Hom.:

AF XY:

0.00000903

AC XY:

AN XY:

110762

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000223

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000839

AC:

AN:

1430672

Hom.:

Cov.:

AF XY:

0.00000847

AC XY:

AN XY:

708246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000518

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000638

Gnomad4 OTH exome

AF:

0.0000507

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary acrodermatitis enteropathica

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2023	Variant summary: SLC39A4 c.283C>T (p.Arg95Cys) results in a non-conservative amino acid change located in the Zinc transporter ZIP4, N-terminal domain (IPR041137) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-06 in 202420 control chromosomes (gnomAD). c.283C>T has been reported in the literature in several compound heterozygous individuals affected with Acrodermatitis Enteropathica (e.g. Nakano_2003, Park_2010, Ichiki_2021). These data indicate that the variant is likely to be associated with disease. When assayed using HEK293 cells, cells transfected with the variant had similar zinc transport activity as cells transfected with an empty vector, indicating total loss of function (Kuliyev_2021). This is presumed to be due to mistrafficking of the protein, which is retained within the ER and not at the cell surface (Kuliyev_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34625996, 33837739, 12787121, 21165302). One ClinVar submitter has assessed the variant since 2014, and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 95 of the SLC39A4 protein (p.Arg95Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acrodermatitis enteropathica (PMID: 12787121, 21165302, 34625996). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3544). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC39A4 function (PMID: 33837739). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T

Eigen

Benign

-0.038

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

.;L

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.41

MutPred

0.84

.;Gain of catalytic residue at L96 (P = 0.0407);

MVP

0.77

MPC

0.65

ClinPred

0.98

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.72

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