2-189565451-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014585.6(SLC40A1):c.663T>C(p.Val221Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,613,956 control chromosomes in the GnomAD database, including 314,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 23598 hom., cov: 33)

Exomes 𝑓: 0.63 ( 291093 hom. )

Consequence

SLC40A1
NM_014585.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.422

Publications

36 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-189565451-A-G is Benign according to our data. Variant chr2-189565451-A-G is described in ClinVar as Benign. ClinVar VariationId is 260422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.422 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6 link	c.663T>C	p.Val221Val	synonymous_variant	Exon 6 of 8	ENST00000261024.7	NP_055400.1	Q9NP59
SLC40A1	XM_047444066.1 link	c.543T>C	p.Val181Val	synonymous_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.663T>C	p.Val221Val	synonymous_variant	Exon 6 of 8	1	NM_014585.6	ENSP00000261024.3		Q9NP59
SLC40A1	ENST00000427241.5 link	c.*62T>C		downstream_gene_variant		5		ENSP00000390005.1		E7ES28

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79693

AN:

152002

Hom.:

23605

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.805

Gnomad AMR

AF:

0.666

Gnomad ASJ

AF:

0.714

Gnomad EAS

AF:

0.802

Gnomad SAS

AF:

0.633

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.625

Gnomad NFE

AF:

0.621

Gnomad OTH

AF:

0.575

GnomAD2 exomes

AF:

0.629

AC:

158018

AN:

251364

AF XY:

0.632

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.747

Gnomad ASJ exome

AF:

0.719

Gnomad EAS exome

AF:

0.792

Gnomad FIN exome

AF:

0.570

Gnomad NFE exome

AF:

0.625

Gnomad OTH exome

AF:

0.646

GnomAD4 exome

AF:

0.626

AC:

915351

AN:

1461834

Hom.:

291093

Cov.:

AF XY:

0.627

AC XY:

456034

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.213

AC:

7138

AN:

33478

American (AMR)

AF:

0.736

AC:

32896

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.720

AC:

18805

AN:

26134

East Asian (EAS)

AF:

0.802

AC:

31832

AN:

39698

South Asian (SAS)

AF:

0.634

AC:

54664

AN:

86256

European-Finnish (FIN)

AF:

0.570

AC:

30425

AN:

53418

Middle Eastern (MID)

AF:

0.634

AC:

3655

AN:

5768

European-Non Finnish (NFE)

AF:

0.628

AC:

698127

AN:

1111966

Other (OTH)

AF:

0.626

AC:

37809

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

21327

42654

63982

85309

106636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18630

37260

55890

74520

93150

<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:

0.524

AC:

79672

AN:

152122

Hom.:

23598

Cov.:

AF XY:

0.529

AC XY:

39329

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.228

AC:

9449

AN:

41484

American (AMR)

AF:

0.666

AC:

10171

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.714

AC:

2478

AN:

3472

East Asian (EAS)

AF:

0.801

AC:

4143

AN:

5172

South Asian (SAS)

AF:

0.632

AC:

3053

AN:

4830

European-Finnish (FIN)

AF:

0.569

AC:

6023

AN:

10578

Middle Eastern (MID)

AF:

0.613

AC:

179

AN:

292

European-Non Finnish (NFE)

AF:

0.621

AC:

42233

AN:

67990

Other (OTH)

AF:

0.572

AC:

1209

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1697

3394

5090

6787

8484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.594

Hom.:

26605

Bravo

AF:

0.522

Asia WGS

AF:

0.674

AC:

2343

AN:

3478

EpiCase

AF:

0.638

EpiControl

AF:

0.635

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hemochromatosis type 4

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.7

(source)

DANN

Benign

0.76

PhyloP100

0.42

Mutation Taster

=100/0

polymorphism (auto)

(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