rs13008848

Variant names:

• chr2-189580558-C-G
• rs13008848
• NM_014585.6:c.-98G>C

Variant summary

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

The NM_014585.6(SLC40A1):​c.-98G>C variant causes a 5 prime UTR 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 NM_014585.6 5_prime_UTR
• 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P, Orphanet, Ambry Genetics

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014585.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	NM_014585.6	MANE Select	c.-98G>C		5_prime_UTR	Exon 1 of 8	NP_055400.1	Q9NP59

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.-98G>C		5_prime_UTR	Exon 1 of 8	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000427419.5	TSL:1	c.-98G>C		5_prime_UTR	Exon 2 of 3	ENSP00000392730.1	Q4PNE6
	SLC40A1	ENST00000440626.1	TSL:1	c.-64-34G>C		intron	N/A	ENSP00000396134.1	Q4PNE6

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hemochromatosis type 4 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;