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rs104893664

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_014585.6(SLC40A1):​c.800G>T​(p.Gly267Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G267D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC40A1
NM_014585.6 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08
Variant links:
Genes affected
SLC40A1 (HGNC:10909): (solute carrier family 40 member 1) The protein encoded by this gene is a cell membrane protein that may be involved in iron export from duodenal epithelial cells. Defects in this gene are a cause of hemochromatosis type 4 (HFE4). [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr2-189564186-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5418.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.12637764).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC40A1NM_014585.6 linkuse as main transcriptc.800G>T p.Gly267Val missense_variant 7/8 ENST00000261024.7
SLC40A1XM_047444066.1 linkuse as main transcriptc.680G>T p.Gly227Val missense_variant 7/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC40A1ENST00000261024.7 linkuse as main transcriptc.800G>T p.Gly267Val missense_variant 7/81 NM_014585.6 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
0.0070
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
15
DANN
Benign
0.88
DEOGEN2
Uncertain
0.51
D
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.67
T
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.74
N
REVEL
Benign
0.23
Sift
Benign
0.17
T
Sift4G
Benign
0.63
T
Polyphen
0.015
B
Vest4
0.24
MutPred
0.39
Gain of sheet (P = 0.0028);
MVP
0.20
MPC
0.60
ClinPred
0.18
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.044
gMVP
0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-190428912; API