rs13008848

Positions:

• chr2-189580558-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate 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. In-silico tool predicts a benign outcome for this variant. 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:2
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 2-189580558-C-G is Benign according to our data. Variant chr2-189580558-C-G is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
SLC40A1	NM_014585.6	c.-98G>C		5_prime_UTR_variant	1/8	ENST00000261024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC40A1	ENST00000261024.7	c.-98G>C		5_prime_UTR_variant	1/8	1	NM_014585.6	P1

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

GnomAD3 exomes AF: 0.166 AC: 38940 AN: 235258 Hom.: 3808 AF XY: 0.172 AC XY: 21978 AN XY: 127772

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 SAS exome AF: 0.148

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

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.0860

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.0475

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.184

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

Gnomad4 AFR AF: 0.0466

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.0489

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.150

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hemochromatosis type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

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