Genetic Variant SLC39A4:p.Gly330Asp (chr8-144414422-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_130849.4(SLC39A4):c.989G>A(p.Gly330Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G330S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.07

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 8-144414422-C-T is Pathogenic according to our data. Variant chr8-144414422-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3542.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A4	NM_130849.4 link	c.989G>A	p.Gly330Asp	missense_variant	Exon 6 of 12	ENST00000301305.8	NP_570901.3	Q6P5W5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC39A4	ENST00000301305.8 link	c.989G>A	p.Gly330Asp	missense_variant	Exon 6 of 12	1	NM_130849.4	ENSP00000301305.4		Q6P5W5-1
SLC39A4	ENST00000276833.9 link	c.914G>A	p.Gly305Asp	missense_variant	Exon 5 of 11	2		ENSP00000276833.5		Q6P5W5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694456

African (AFR)

AF:

0.00

AC:

AN:

32198

American (AMR)

AF:

0.00

AC:

AN:

35906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25228

East Asian (EAS)

AF:

0.00

AC:

AN:

37096

South Asian (SAS)

AF:

0.00

AC:

AN:

79862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083740

Other (OTH)

AF:

0.00

AC:

AN:

58342

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hereditary acrodermatitis enteropathica

Pathogenic:1

Jul 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

.;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.3

.;M

PhyloP100

1.1

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0060

D;T

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.85

MutPred

0.93

.;Loss of catalytic residue at Y329 (P = 0.0954);

MVP

0.72

MPC

0.65

ClinPred

0.98

GERP RS

5.0

Varity_R

0.75

gMVP

0.80

Mutation Taster

=18/82

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over