chr2-218384312-G-C

Variant summary

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

The NM_000578.4(SLC11A1):ā€‹c.220G>Cā€‹(p.Asp74His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,442 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 (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

SLC11A1
NM_000578.4 missense

Scores

15
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.72
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, 0.933

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC11A1NM_000578.4 linkuse as main transcriptc.220G>C p.Asp74His missense_variant 3/15 ENST00000233202.11 NP_000569.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC11A1ENST00000233202.11 linkuse as main transcriptc.220G>C p.Asp74His missense_variant 3/151 NM_000578.4 ENSP00000233202 P1P49279-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249354
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134816
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 SAS exome
AF:
0.0000330
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1456442
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
724744
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

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 GeneticsJun 06, 2023The c.220G>C (p.D74H) alteration is located in exon 3 (coding exon 3) of the SLC11A1 gene. This alteration results from a G to C substitution at nucleotide position 220, causing the aspartic acid (D) at amino acid position 74 to be replaced by a histidine (H). 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.080
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-6.7
D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.74
Loss of catalytic residue at D74 (P = 0.0999);
MVP
0.91
MPC
0.60
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.97
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.21
Position offset: 7

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: rs778334000; hg19: chr2-219249035; API