Genetic Variant SLC39A4:p.Pro200Arg (chr8-144415295-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_130849.4(SLC39A4):c.599C>G(p.Pro200Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,920 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P200L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-144415295-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A4	NM_130849.4 link	c.599C>G	p.Pro200Arg	missense_variant	Exon 3 of 12	ENST00000301305.8	NP_570901.3	Q6P5W5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC39A4	ENST00000301305.8 link	c.599C>G	p.Pro200Arg	missense_variant	Exon 3 of 12	1	NM_130849.4	ENSP00000301305.4	Q6P5W5-1
SLC39A4	ENST00000276833.9 link	c.524C>G	p.Pro175Arg	missense_variant	Exon 2 of 11	2		ENSP00000276833.5	Q6P5W5-2
SLC39A4	ENST00000526658.1 link	c.317C>G	p.Pro106Arg	missense_variant	Exon 2 of 4	3		ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726776

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111856

Other (OTH)

AF:

0.00

AC:

AN:

60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

.;T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.77

T;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

.;L;.

PhyloP100

1.7

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Benign

0.29

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;.

Vest4

0.66

MutPred

0.61

.;Loss of catalytic residue at Q203 (P = 0.137);.;

MVP

0.82

MPC

0.61

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.67

Mutation Taster

=41/59

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over