chr8-144414342-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130849.4(SLC39A4):c.1069A>G(p.Thr357Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,593,756 control chromosomes in the GnomAD database, including 244,503 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T357I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 17741 hom., cov: 33)

Exomes 𝑓: 0.56 ( 226762 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.92

Publications

35 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.79509E-5).

BP6

Variant 8-144414342-T-C is Benign according to our data. Variant chr8-144414342-T-C is described in ClinVar as Benign. ClinVar VariationId is 362242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

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.1069A>G	p.Thr357Ala	missense	Exon 6 of 12	NP_570901.3
SLC39A4	NM_017767.3		c.994A>G	p.Thr332Ala	missense	Exon 5 of 11	NP_060237.3
SLC39A4	NM_001374839.1		c.787A>G	p.Thr263Ala	missense	Exon 5 of 11	NP_001361768.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.1069A>G	p.Thr357Ala	missense	Exon 6 of 12	ENSP00000301305.4
	SLC39A4	ENST00000276833.9	TSL:2	c.994A>G	p.Thr332Ala	missense	Exon 5 of 11	ENSP00000276833.5

Frequencies

GnomAD3 genomes

AF:

0.443

AC:

67273

AN:

151896

Hom.:

17751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.595

Gnomad EAS

AF:

0.512

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.611

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.580

Gnomad OTH

AF:

0.475

GnomAD2 exomes

AF:

0.519

AC:

111737

AN:

215224

AF XY:

0.526

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.459

Gnomad ASJ exome

AF:

0.593

Gnomad EAS exome

AF:

0.511

Gnomad FIN exome

AF:

0.599

Gnomad NFE exome

AF:

0.581

Gnomad OTH exome

AF:

0.554

GnomAD4 exome

AF:

0.555

AC:

800405

AN:

1441742

Hom.:

226762

Cov.:

AF XY:

0.553

AC XY:

395587

AN XY:

715052

show subpopulations

African (AFR)

AF:

0.116

AC:

3855

AN:

33356

American (AMR)

AF:

0.458

AC:

18366

AN:

40086

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

15111

AN:

25640

East Asian (EAS)

AF:

0.486

AC:

18984

AN:

39032

South Asian (SAS)

AF:

0.467

AC:

38690

AN:

82838

European-Finnish (FIN)

AF:

0.601

AC:

30834

AN:

51266

Middle Eastern (MID)

AF:

0.561

AC:

3205

AN:

5712

European-Non Finnish (NFE)

AF:

0.579

AC:

638980

AN:

1104040

Other (OTH)

AF:

0.542

AC:

32380

AN:

59772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

23395

46789

70184

93578

116973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17444

34888

52332

69776

87220

<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:

0.443

AC:

67283

AN:

152014

Hom.:

17741

Cov.:

AF XY:

0.444

AC XY:

32995

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.136

AC:

5633

AN:

41456

American (AMR)

AF:

0.463

AC:

7065

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.595

AC:

2061

AN:

3464

East Asian (EAS)

AF:

0.513

AC:

2649

AN:

5162

South Asian (SAS)

AF:

0.477

AC:

2301

AN:

4822

European-Finnish (FIN)

AF:

0.611

AC:

6483

AN:

10602

Middle Eastern (MID)

AF:

0.527

AC:

154

AN:

292

European-Non Finnish (NFE)

AF:

0.580

AC:

39369

AN:

67922

Other (OTH)

AF:

0.474

AC:

999

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1687

3374

5062

6749

8436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.541

Hom.:

32469

Bravo

AF:

0.422

TwinsUK

AF:

0.568

AC:

2105

ALSPAC

AF:

0.565

AC:

2178

ESP6500AA

AF:

0.147

AC:

644

ESP6500EA

AF:

0.577

AC:

4952

ExAC

AF:

0.483

AC:

56967

Asia WGS

AF:

0.494

AC:

1718

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary acrodermatitis enteropathica (4)

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.033

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.27

MetaRNN

Benign

0.000088

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.84

PhyloP100

1.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.73

REVEL

Benign

0.043

Sift

Benign

0.28

Sift4G

Benign

0.52

Polyphen

0.012

Vest4

0.015

MPC

0.13

ClinPred

0.013

GERP RS

-0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.11

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over