Genetic Variant SLC39A4:p.Ala114Ser (chr8-144415944-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_130849.4(SLC39A4):c.340G>T(p.Ala114Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. A114T) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.383

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: Genomics England PanelApp, Ambry Genetics, Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen

SLC39A4 links:

LOC124902041 (HGNC:):

LOC124902041 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05485931).

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	UniProt
SLC39A4	NM_130849.4	MANE Select	c.340G>T	p.Ala114Ser	missense	Exon 2 of 12	NP_570901.3	Q6P5W5-1
SLC39A4	NM_017767.3		c.265G>T	p.Ala89Ser	missense	Exon 1 of 11	NP_060237.3	Q6P5W5-2
SLC39A4	NM_001374839.1		c.193-525G>T		intron	N/A	NP_001361768.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.340G>T	p.Ala114Ser	missense	Exon 2 of 12	ENSP00000301305.4	Q6P5W5-1
SLC39A4	ENST00000276833.9	TSL:2	c.265G>T	p.Ala89Ser	missense	Exon 1 of 11	ENSP00000276833.5	Q6P5W5-2
SLC39A4	ENST00000526658.1	TSL:3	c.193-525G>T		intron	N/A	ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440326

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33336

American (AMR)

AF:

0.00

AC:

AN:

41662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25684

East Asian (EAS)

AF:

0.00

AC:

AN:

39040

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104022

Other (OTH)

AF:

0.00

AC:

AN:

59596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

5.3

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.018

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PhyloP100

-0.38

PrimateAI

Benign

0.40

PROVEAN

Benign

0.31

REVEL

Benign

0.046

Sift

Benign

0.88

Sift4G

Uncertain

0.047

Polyphen

0.41

Vest4

0.047

MutPred

0.31

Gain of glycosylation at A114 (P = 0.0317)

MVP

0.23

MPC

0.35

ClinPred

0.088

GERP RS

-3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over