Genetic Variant NM_000578.4:c.256G>T (chr2-218384348-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

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>T(p.Ala86Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,302 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. A86T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC11A1
NM_000578.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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

SLC11A1 links:

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, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC11A1	NM_000578.4 link	c.256G>T	p.Ala86Ser	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
SLC11A1	ENST00000233202.11 link	c.256G>T	p.Ala86Ser	missense_variant	Exon 3 of 15	1	NM_000578.4	ENSP00000233202.6		P49279-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000806

AC:

AN:

248272

AF XY:

0.0000149

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1452302

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33278

American (AMR)

AF:

0.00

AC:

AN:

44292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

39344

South Asian (SAS)

AF:

0.0000351

AC:

AN:

85452

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105332

Other (OTH)

AF:

0.00

AC:

AN:

59802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.1

PhyloP100

9.4

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.54

Sift

Uncertain

0.024

Sift4G

Uncertain

0.035

Polyphen

0.86

Vest4

0.84

MutPred

0.86

Gain of disorder (P = 0.0407);

MVP

0.81

MPC

0.53

ClinPred

0.94

GERP RS

5.1

Varity_R

0.34

gMVP

0.65

Mutation Taster

=187/113

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over