rs11568351

chr2-189580468-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014585.6(SLC40A1):c.-8C>G 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 1,613,064 control chromosomes in the GnomAD database, including 35,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2429 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33311 hom.)
• Consequence: SLC40A1 NM_014585.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-189580468-G-C is Benign according to our data. Variant chr2-189580468-G-C is described in ClinVar as [Benign]. Clinvar id is 260420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23827 AN: 151984 Hom.: 2429 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.168 AC: 42131 AN: 250830 Hom.: 4363 AF XY: 0.174 AC XY: 23628 AN XY: 135620

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.0810

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0366

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.206 AC: 301420 AN: 1460962 Hom.: 33311 Cov.: 35 AF XY: 0.206 AC XY: 149601 AN XY: 726830

Gnomad4 AFR exome AF: 0.0390

Gnomad4 AMR exome AF: 0.0861

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.0369

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.157 AC: 23826 AN: 152102 Hom.: 2429 Cov.: 32 AF XY: 0.155 AC XY: 11499 AN XY: 74366

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0402

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.149

Alfa AF: 0.199 Hom.: 1060

Bravo AF: 0.140

Asia WGS AF: 0.0960 AC: 335 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	-0.62
Cadd	Benign	17
Dann	Benign	0.90

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: rs11568351; hg19: chr2-190445194; COSMIC: COSV53722527;