2-218384348-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000578.4(SLC11A1):​c.256G>A​(p.Ala86Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,604,490 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A86S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC11A1
NM_000578.4 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.45

Publications

4 publications found
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]
SLC11A1 Gene-Disease associations (from GenCC):
  • cystic fibrosis
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC11A1NM_000578.4 linkc.256G>A p.Ala86Thr missense_variant Exon 3 of 15 ENST00000233202.11 NP_000569.3 P49279-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC11A1ENST00000233202.11 linkc.256G>A p.Ala86Thr missense_variant Exon 3 of 15 1 NM_000578.4 ENSP00000233202.6 P49279-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152190
Hom.:
0
Cov.:
31
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000201
AC:
5
AN:
248272
AF XY:
0.0000372
show subpopulations
Gnomad AFR exome
AF:
0.0000624
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000553
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000124
AC:
18
AN:
1452300
Hom.:
0
Cov.:
31
AF XY:
0.0000180
AC XY:
13
AN XY:
722532
show subpopulations
African (AFR)
AF:
0.0000300
AC:
1
AN:
33278
American (AMR)
AF:
0.00
AC:
0
AN:
44292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25892
East Asian (EAS)
AF:
0.0000763
AC:
3
AN:
39344
South Asian (SAS)
AF:
0.0000585
AC:
5
AN:
85452
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53186
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5724
European-Non Finnish (NFE)
AF:
0.00000724
AC:
8
AN:
1105330
Other (OTH)
AF:
0.0000167
AC:
1
AN:
59802
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152190
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000241
AC:
1
AN:
41436
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:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68048
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.001814), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.342
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.256G>A (p.A86T) alteration is located in exon 3 (coding exon 3) of the SLC11A1 gene. This alteration results from a G to A substitution at nucleotide position 256, causing the alanine (A) at amino acid position 86 to be replaced by a threonine (T). 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
Benign
0.22
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.75
D
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.095
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Uncertain
2.8
M
PhyloP100
9.4
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.0
N
REVEL
Pathogenic
0.71
Sift
Uncertain
0.024
D
Sift4G
Uncertain
0.034
D
Polyphen
0.97
D
Vest4
0.93
MutPred
0.84
Gain of methylation at K91 (P = 0.0637);
MVP
0.88
MPC
0.55
ClinPred
0.86
D
GERP RS
5.1
Varity_R
0.34
gMVP
0.79
Mutation Taster
=187/113
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: rs760595815; hg19: chr2-219249071; COSMIC: COSV51917443; COSMIC: COSV51917443; API