rs13008848

Variant names:

• chr2-189580558-C-G
• rs13008848
• ENST00000479598.5:n.184G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000479598.5(SLC40A1):​n.184G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,601,060 control chromosomes in the GnomAD database, including 35,289 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2425 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32864 hom.)
• Consequence: SLC40A1 ENST00000479598.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.62
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-189580558-C-G is Benign according to our data. Variant chr2-189580558-C-G is described in ClinVar as Benign. ClinVar VariationId is 260421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.-98G>C		5_prime_UTR_variant	Exon 1 of 8	ENST00000261024.7	NP_055400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.-98G>C		5_prime_UTR_variant	Exon 1 of 8	1	NM_014585.6	ENSP00000261024.3

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23809 AN: 152086 Hom.: 2424 Cov.: 33

Gnomad AFR AF: 0.0467

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0492

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.166 AC: 38940 AN: 235258 AF XY: 0.172

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.0812

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0448

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.206 AC: 298890 AN: 1448854 Hom.: 32864 Cov.: 34 AF XY: 0.206 AC XY: 148279 AN XY: 720772

African (AFR) AF: 0.0393 AC: 1311 AN: 33392

American (AMR) AF: 0.0860 AC: 3786 AN: 44018

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3285 AN: 26054

East Asian (EAS) AF: 0.0475 AC: 1880 AN: 39586

South Asian (SAS) AF: 0.150 AC: 12878 AN: 85892

European-Finnish (FIN) AF: 0.238 AC: 10515 AN: 44224

Middle Eastern (MID) AF: 0.158 AC: 913 AN: 5764

European-Non Finnish (NFE) AF: 0.228 AC: 253248 AN: 1109724

Other (OTH) AF: 0.184 AC: 11074 AN: 60200

GnomAD4 genome AF: 0.156 AC: 23809 AN: 152206 Hom.: 2425 Cov.: 33 AF XY: 0.154 AC XY: 11485 AN XY: 74408

African (AFR) AF: 0.0466 AC: 1938 AN: 41548

American (AMR) AF: 0.118 AC: 1805 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3470

East Asian (EAS) AF: 0.0489 AC: 253 AN: 5176

South Asian (SAS) AF: 0.147 AC: 708 AN: 4826

European-Finnish (FIN) AF: 0.243 AC: 2574 AN: 10584

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15632 AN: 67988

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.190 Hom.: 560

Bravo AF: 0.140

Asia WGS AF: 0.102 AC: 356 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemochromatosis type 4 Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.91
PhyloP100		1.6
PromoterAI		0.0016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=298/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13008848; hg19: chr2-190445284; COSMIC: COSV53722536;