NM_001128225.3:c.640A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001128225.3(SLC39A13):​c.640A>G​(p.Ile214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I214I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SLC39A13
NM_001128225.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.540

Publications

1 publications found
Variant links:
Genes affected
SLC39A13 (HGNC:20859): (solute carrier family 39 member 13) This gene encodes a member of the LIV-1 subfamily of the ZIP transporter family. The encoded transmembrane protein functions as a zinc transporter. Mutations in this gene have been associated with the spondylocheiro dysplastic form of Ehlers-Danlos syndrome. Alternate transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]
SLC39A13 Gene-Disease associations (from GenCC):
  • Ehlers-Danlos syndrome, spondylocheirodysplastic type
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Orphanet, Genomics England PanelApp
  • spondyloepimetaphyseal dysplasia-abnormal dentition syndrome
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (MetaRNN=0.07509923).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC39A13NM_001128225.3 linkc.640A>G p.Ile214Val missense_variant Exon 5 of 10 ENST00000362021.9 NP_001121697.2 Q96H72-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC39A13ENST00000362021.9 linkc.640A>G p.Ile214Val missense_variant Exon 5 of 10 1 NM_001128225.3 ENSP00000354689.4 Q96H72-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000319
AC:
8
AN:
250526
AF XY:
0.0000295
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000707
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000106
AC:
155
AN:
1461756
Hom.:
0
Cov.:
34
AF XY:
0.0000990
AC XY:
72
AN XY:
727198
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53360
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000118
AC:
131
AN:
1111984
Other (OTH)
AF:
0.000397
AC:
24
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
10
19
29
38
48
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74380
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000587
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jan 18, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 14, 2020
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function -

Inborn genetic diseases Uncertain:1
Feb 23, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.640A>G (p.I214V) alteration is located in exon 5 (coding exon 4) of the SLC39A13 gene. This alteration results from a A to G substitution at nucleotide position 640, causing the isoleucine (I) at amino acid position 214 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Ehlers-Danlos syndrome, spondylocheirodysplastic type Uncertain:1
Oct 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 214 of the SLC39A13 protein (p.Ile214Val). This variant is present in population databases (rs750123189, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SLC39A13-related conditions. ClinVar contains an entry for this variant (Variation ID: 452828). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC39A13 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.010
T;T;.;.;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.43
N
LIST_S2
Benign
0.61
T;T;T;T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.075
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
.;L;L;.;.
PhyloP100
0.54
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.34
N;N;N;N;N
REVEL
Benign
0.076
Sift
Benign
0.11
T;T;T;T;T
Sift4G
Benign
0.30
T;T;T;T;T
Polyphen
0.0010, 0.051
.;B;B;.;B
Vest4
0.056
MVP
0.38
MPC
0.29
ClinPred
0.034
T
GERP RS
1.8
Varity_R
0.049
gMVP
0.22
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs750123189; hg19: chr11-47435053; API