rs11568350

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6 linkuse as main transcript	c.744G>T	p.Gln248His	missense_variant	6/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1 linkuse as main transcript	c.624G>T	p.Gln208His	missense_variant	6/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7 linkuse as main transcript	c.744G>T	p.Gln248His	missense_variant	6/8	1	NM_014585.6	ENSP00000261024	P1

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

GnomAD3 exomes

AF:

0.00378

AC:

951

AN:

251364

Hom.:

AF XY:

0.00249

AC XY:

338

AN XY:

135876

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 SAS exome

AF:

0.000196

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

Gnomad4 AFR exome

AF:

0.0514

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.00336

GnomAD4 genome

AF:

0.0146

AC:

2227

AN:

152346

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1019

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0507

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.00302

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over