chr8-144414291-C-T

Position:

chr8-144414291-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_130849.4(SLC39A4):c.1120G>A(p.Gly374Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,608,690 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 Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.35

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 8-144414291-C-T is Pathogenic according to our data. Variant chr8-144414291-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3539.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144414291-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A4	NM_130849.4 linkuse as main transcript	c.1120G>A	p.Gly374Arg	missense_variant	6/12	ENST00000301305.8	NP_570901.3	Q6P5W5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A4	ENST00000301305.8 linkuse as main transcript	c.1120G>A	p.Gly374Arg	missense_variant	6/12	1	NM_130849.4	ENSP00000301305.4		Q6P5W5-1
SLC39A4	ENST00000276833.9 linkuse as main transcript	c.1045G>A	p.Gly349Arg	missense_variant	5/11	2		ENSP00000276833.5		Q6P5W5-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000210

AC:

AN:

237714

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

128424

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:

0.0000463

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1456576

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

723982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000432

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary acrodermatitis enteropathica

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2002

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SLC39A4 function (PMID: 14709598). 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. ClinVar contains an entry for this variant (Variation ID: 3539). This missense change has been observed in individual(s) with acrodermatitis enteropathica (PMID: 12068297, 26351177). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121434289, gnomAD 0.005%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 374 of the SLC39A4 protein (p.Gly374Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

4.2

.;H

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.90

MutPred

0.97

.;Gain of methylation at G374 (P = 0.023);

MVP

0.79

MPC

0.64

ClinPred

0.95

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.86

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

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