2-218385240-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000578.4(SLC11A1):​c.367G>A​(p.Glu123Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

SLC11A1
NM_000578.4 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62
Variant links:
Genes affected
SLC11A1 (HGNC:10907): (solute carrier family 11 member 1) This gene is a member of the solute carrier family 11 (proton-coupled divalent metal ion transporters) family and encodes a multi-pass membrane protein. The protein functions as a divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. Mutations in this gene have been associated with susceptibility to infectious diseases such as tuberculosis and leprosy, and inflammatory diseases such as rheumatoid arthritis and Crohn disease. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC11A1NM_000578.4 linkuse as main transcriptc.367G>A p.Glu123Lys missense_variant 4/15 ENST00000233202.11 NP_000569.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC11A1ENST00000233202.11 linkuse as main transcriptc.367G>A p.Glu123Lys missense_variant 4/151 NM_000578.4 ENSP00000233202 P1P49279-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
251112
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135712
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000438
AC:
64
AN:
1461658
Hom.:
0
Cov.:
31
AF XY:
0.0000399
AC XY:
29
AN XY:
727142
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152336
Hom.:
0
Cov.:
32
AF XY:
0.0000671
AC XY:
5
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 15, 2023The c.367G>A (p.E123K) alteration is located in exon 4 (coding exon 4) of the SLC11A1 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the glutamic acid (E) at amino acid position 123 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
D
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Uncertain
-0.039
T
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.6
D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.071
T
Polyphen
0.82
P
Vest4
0.91
MVP
0.92
MPC
0.47
ClinPred
0.68
D
GERP RS
5.1
Varity_R
0.54
gMVP
0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375958099; hg19: chr2-219249963; API