8-144416001-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R95R) has been classified as Likely benign.

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

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

acrodermatitis enteropathica
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

SLC39A4 links:

LOC124902041 (HGNC:):

LOC124902041 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 3544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC39A4	NM_130849.4	MANE Select	c.283C>T	p.Arg95Cys	missense	Exon 2 of 12	NP_570901.3
SLC39A4	NM_017767.3		c.208C>T	p.Arg70Cys	missense	Exon 1 of 11	NP_060237.3
SLC39A4	NM_001374839.1		c.193-582C>T		intron	N/A	NP_001361768.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.283C>T	p.Arg95Cys	missense	Exon 2 of 12	ENSP00000301305.4
SLC39A4	ENST00000276833.9	TSL:2	c.208C>T	p.Arg70Cys	missense	Exon 1 of 11	ENSP00000276833.5
SLC39A4	ENST00000526658.1	TSL:3	c.193-582C>T		intron	N/A	ENSP00000434512.1

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

GnomAD2 exomes

AF:

0.00000988

AC:

AN:

202420

AF XY:

0.00000903

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 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

African (AFR)

AF:

0.00

AC:

AN:

33124

American (AMR)

AF:

0.00

AC:

AN:

41032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25540

East Asian (EAS)

AF:

0.0000518

AC:

AN:

38612

South Asian (SAS)

AF:

0.00

AC:

AN:

83438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000638

AC:

AN:

1097964

Other (OTH)

AF:

0.0000507

AC:

AN:

59176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary acrodermatitis enteropathica (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.038

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

PhyloP100

2.9

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

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

Mutation Taster

=94/6

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over