Genetic Variant SLC39A4:p.Asn106Lys (chr8-144415966-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PS1PM2BP4_Moderate

The NM_130849.4(SLC39A4):c.318C>G(p.Asn106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N106N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.220

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PS1

Transcript NM_130849.4 (SLC39A4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 3540

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14926004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A4	NM_130849.4 link	c.318C>G	p.Asn106Lys	missense_variant	Exon 2 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.318C>G	p.Asn106Lys	missense_variant	Exon 2 of 12	1	NM_130849.4	ENSP00000301305.4	Q6P5W5-1
SLC39A4	ENST00000276833.9 link	c.243C>G	p.Asn81Lys	missense_variant	Exon 1 of 11	2		ENSP00000276833.5	Q6P5W5-2
SLC39A4	ENST00000526658.1 link	c.193-547C>G		intron_variant	Intron 1 of 3	3		ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

42184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25688

East Asian (EAS)

AF:

0.00

AC:

AN:

39106

South Asian (SAS)

AF:

0.00

AC:

AN:

84052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105326

Other (OTH)

AF:

0.00

AC:

AN:

59700

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L

PhyloP100

0.22

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.083

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.42

.;B

Vest4

0.084

MutPred

0.41

.;Gain of ubiquitination at N106 (P = 0.0192);

MVP

0.53

MPC

0.25

ClinPred

0.28

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.61

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

8-144415966-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over