rs11568350

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014585.6(SLC40A1):c.744G>T(p.Gln248His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,614,214 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q248L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 52 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 48 hom. )

Consequence

SLC40A1
NM_014585.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.232

Publications

51 publications found

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]

SLC40A1 Gene-Disease associations (from GenCC):

hemochromatosis type 4
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

SLC40A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053548813).

BP6

Variant 2-189565370-C-A is Benign according to our data. Variant chr2-189565370-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2227/152346) while in subpopulation AFR AF = 0.0507 (2108/41582). AF 95% confidence interval is 0.0489. There are 52 homozygotes in GnomAd4. There are 1019 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 52 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6 link	c.744G>T	p.Gln248His	missense_variant	Exon 6 of 8	ENST00000261024.7	NP_055400.1	Q9NP59
SLC40A1	XM_047444066.1 link	c.624G>T	p.Gln208His	missense_variant	Exon 6 of 8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7 link	c.744G>T	p.Gln248His	missense_variant	Exon 6 of 8	1	NM_014585.6	ENSP00000261024.3		Q9NP59
SLC40A1	ENST00000427241.5 link	c.*143G>T		downstream_gene_variant		5		ENSP00000390005.1		E7ES28

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2217

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

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:

0.000132

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00378

AC:

951

AN:

251364

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.0528

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00143

AC:

2089

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

844

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0514

AC:

1721

AN:

33476

American (AMR)

AF:

0.00239

AC:

107

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1112002

Other (OTH)

AF:

0.00336

AC:

203

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0146

AC:

2227

AN:

152346

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1019

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0507

AC:

2108

AN:

41582

American (AMR)

AF:

0.00562

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68030

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00576

Hom.:

Bravo

AF:

0.0168

ESP6500AA

AF:

0.0581

AC:

256

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00468

AC:

568

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 4

Benign:2

Feb 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.57

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.58

MutationAssessor

Benign

2.0

PhyloP100

0.23

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.34

Sift

Benign

0.13

Sift4G

Benign

0.22

Polyphen

0.010

Vest4

0.098

MutPred

0.067

Loss of helix (P = 0.2022);

MVP

0.50

MPC

0.45

ClinPred

0.0097

GERP RS

0.59

Varity_R

0.096

gMVP

0.63

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over