Genetic Variant NM_130849.4:c.318C>A (chr8-144415966-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_130849.4(SLC39A4):c.318C>A(p.Asn106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). 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: 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: 0.220

Publications

6 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-144415966-G-T is Pathogenic according to our data. Variant chr8-144415966-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3540.Status of the report is no_assertion_criteria_provided, 0 stars.

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.318C>A	p.Asn106Lys	missense	Exon 2 of 12	NP_570901.3
SLC39A4	NM_017767.3		c.243C>A	p.Asn81Lys	missense	Exon 1 of 11	NP_060237.3
SLC39A4	NM_001374839.1		c.193-547C>A		intron	N/A	NP_001361768.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.318C>A	p.Asn106Lys	missense	Exon 2 of 12	ENSP00000301305.4
SLC39A4	ENST00000276833.9	TSL:2	c.243C>A	p.Asn81Lys	missense	Exon 1 of 11	ENSP00000276833.5
SLC39A4	ENST00000526658.1	TSL:3	c.193-547C>A		intron	N/A	ENSP00000434512.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716466

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:

0.00

AC:

AN:

1105326

Other (OTH)

AF:

0.00

AC:

AN:

59700

GnomAD4 genome

Cov.:

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 v4.9

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

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PhyloP100

0.22

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.083

Sift

Uncertain

0.010

Sift4G

Uncertain

0.015

Polyphen

0.42

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

Varity_R

0.062

gMVP

0.61

Mutation Taster

=39/61

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over